U.S. patent application number 15/015563 was filed with the patent office on 2016-08-11 for thienopyrimidinones as ubiquitin-specific protease 7 inhibitors.
The applicant listed for this patent is Forma Therapeutics, Inc.. Invention is credited to Alexandre Joseph Buckmelter, Ann-Marie Campbell, Bruce Follows, Stephanos Ioannidis, David Lancia, JR., Adam Charles Talbot, Minghua Wang.
Application Number | 20160229864 15/015563 |
Document ID | / |
Family ID | 55404832 |
Filed Date | 2016-08-11 |
United States Patent
Application |
20160229864 |
Kind Code |
A1 |
Ioannidis; Stephanos ; et
al. |
August 11, 2016 |
THIENOPYRIMIDINONES AS UBIQUITIN-SPECIFIC PROTEASE 7 INHIBITORS
Abstract
The disclosure relates to inhibitors of USP7 inhibitors useful
in the treatment of cancers, neurodegenerative diseases,
immunological disorders, inflammatory disorders, cardiovascular
diseases, ischemic diseases, viral infections and diseases, and
bacterial infections and diseases, having the Formula: ##STR00001##
where R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.5', X.sub.1,
X.sub.2, n, and m are described herein.
Inventors: |
Ioannidis; Stephanos;
(Natick, MA) ; Talbot; Adam Charles; (Guilford,
CT) ; Follows; Bruce; (Littleton, MA) ;
Buckmelter; Alexandre Joseph; (Acton, MA) ; Wang;
Minghua; (Acton, MA) ; Campbell; Ann-Marie;
(Monroe, CT) ; Lancia, JR.; David; (Boston,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Forma Therapeutics, Inc. |
Watertown |
MA |
US |
|
|
Family ID: |
55404832 |
Appl. No.: |
15/015563 |
Filed: |
February 4, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62112482 |
Feb 5, 2015 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/02 20180101;
A61P 25/00 20180101; Y02A 50/463 20180101; A61P 35/00 20180101;
A61P 37/00 20180101; Y02A 50/30 20180101; A61P 43/00 20180101; A61K
31/519 20130101; A61P 37/02 20180101; A61P 31/12 20180101; A61P
31/00 20180101; A61P 29/02 20180101; C07D 495/04 20130101 |
International
Class: |
C07D 495/04 20060101
C07D495/04 |
Claims
1. A compound of Formula (I): ##STR00040## or a pharmaceutically
acceptable salt, hydrate, solvate, prodrug, stereoisomer, and
tautomer thereof, wherein: X.sub.1 is C, S, or S(O); X.sub.2 is
##STR00041## R.sub.1 is H, --OH, --SH, --NH.sub.2, or F; R.sub.2 is
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl is
substituted with one or more R.sub.8, and wherein the aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8; each R.sub.3 is independently
at each occurrence selected from D, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.20; or two R.sub.3 together when on adjacent
carbons form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted
with one or more R.sub.20; or two R.sub.3 together when attached to
the same carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when attached to the same carbon atom form a
spiroheterocycloalkyl optionally substituted with one or more
R.sub.20; or two R.sub.3 together when on adjacent carbons form an
aryl ring optionally substituted with one or more R.sub.20; or two
R.sub.3 together when on adjacent carbons form an heteroaryl ring
optionally substituted with one or more R.sub.20; R.sub.4 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.12; R.sub.5 and
R.sub.5' are independently H, D, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, or CN; R.sub.6 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl, halogen,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.14; R.sub.7 is H, D,
(C.sub.1-C.sub.6) alkyl, halogen, CN, NO.sub.2, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.16; or R.sub.6 and R.sub.7 together with the atoms to which
they are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16; each R.sub.8 is
independently D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted with one
or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a heterocycloalkyl ring optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form
an aryl ring optionally substituted with one or more R.sub.9; or
two R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9; each R.sub.9 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, --NH.sub.2, --OH, --C(O)R.sub.23,
--C(O)NR.sub.23R.sub.24, --NR.sub.23C(O)R.sub.24,
--NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26; R.sub.10 and
R.sub.11 are independently H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.18; or R.sub.10 and R.sub.11 together with the
nitrogen to which they are attached form a heterocycloalkyl ring
optionally substituted with one or more R.sub.18; each R.sub.12 is
independently D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --OH, --NH.sub.2, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl,
--O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13; each R.sub.13 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or
CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.29; each R.sub.14 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.15; each R.sub.15 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.16 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6)
alkyl, --NH.sub.2, --OH, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.17; each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN; each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19; each R.sub.19 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.20 is independently at each
occurrence (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN; each R.sub.21 and R.sub.22 is
independently H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocycloalkyl are optionally substituted with one or more
R.sub.25; each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25; each R.sub.25 is
independently at each occurrence (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN; each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN; each R.sub.27 and R.sub.28
is independently at each occurrence H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one or more substituents independently selected
from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, or di(C.sub.1-C.sub.6)
alkylamino; each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3;
and q is independently at each occurrence 0, 1, or 2.
2. The compound of claim 1, wherein X.sub.1 is C.
3. The compound of claim 1, wherein R.sub.1 is --OH.
4. The compound of claim 1, wherein R.sub.4 is (C.sub.6-C.sub.14)
aryl or heteroaryl.
5. The compound of claim 1, wherein R.sub.5 is H.
6. The compound of claim 1, wherein R.sub.5' is H.
7. The compound of claim 1, wherein is R.sub.6 is H,
(C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl.
8. The compound of claim 1, wherein R.sub.7 is H, (C.sub.1-C.sub.6)
alkyl, or (C.sub.6-C.sub.14) aryl.
9. The compound of claim 1, wherein R.sub.6 and R.sub.7 together
with the atoms to which they are attached form a
(C.sub.3-C.sub.8)cycloalkyl optionally substituted with one or more
R.sub.16.
10. The compound of claim 1, wherein n is 1.
11. The compound of claim 1, having Formula (Ia), Formula (Ic),
Formula (Ie), or Formula (Ig): ##STR00042## or a pharmaceutically
acceptable salt, hydrate, solvate, prodrug, stereoisomer, and
tautomer thereof, wherein: X.sub.1 is C, S, or S(O); R.sub.1 is H,
--OH, --SH, --NH.sub.2, or F; R.sub.2 is (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
heterocycloalkyl, --NR.sub.10R.sub.11, or --OR.sub.10, wherein the
alkyl is substituted with one or more R.sub.8, and wherein the
aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8; each R.sub.3 is independently
at each occurrence selected from D, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.20; or two R.sub.3 together when on adjacent
carbons form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted
with one or more R.sub.20; or two R.sub.3 together when attached to
the same carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when attached to the same carbon atom form a
spiroheterocycloalkyl optionally substituted with one or more
R.sub.20; or two R.sub.3 together when on adjacent carbons form an
aryl ring optionally substituted with one or more R.sub.20; or two
R.sub.3 together when on adjacent carbons form an heteroaryl ring
optionally substituted with one or more R.sub.20; R.sub.4 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.12; R.sub.5 and
R.sub.5' are independently H, D, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, or CN; R.sub.7 is H, D,
(C.sub.1-C.sub.6) alkyl, halogen, CN, NO.sub.2, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.16; each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted with one
or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a heterocycloalkyl ring optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form
an aryl ring optionally substituted with one or more R.sub.9; or
two R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9; each R.sub.9 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, --NH.sub.2, --OH, --C(O)R.sub.23,
--C(O)NR.sub.23R.sub.24, --NR.sub.23C(O)R.sub.24,
--NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26; R.sub.10 and
R.sub.11 are independently H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.18; or R.sub.10 and R.sub.11 together with the
nitrogen to which they are attached form a heterocycloalkyl ring
optionally substituted with one or more R.sub.18; each R.sub.12 is
independently D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --OH, --NH.sub.2, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl,
--O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13; each R.sub.13 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or
CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.29; each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17; each R.sub.17 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.18 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.1-C.sub.6) hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19; each R.sub.19 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.20 is independently at each
occurrence (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN; each R.sub.21 and R.sub.22 is
independently H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocycloalkyl are optionally substituted with one or more
R.sub.25; each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25; each R.sub.25 is
independently at each occurrence (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN; each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN; each R.sub.27 and R.sub.28
is independently at each occurrence H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one or more substituents independently selected
from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, or di(C.sub.1-C.sub.6)
alkylamino; each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3;
and q is independently at each occurrence 0, 1, or 2.
12. The compound of claim 1, having Formula (Ib), Formula (Id),
Formula (If), or Formula (Ih): ##STR00043## or a pharmaceutically
acceptable salt, hydrate, solvate, prodrug, stereoisomer, and
tautomer thereof, wherein: X.sub.1 is C, S, or S(O); R.sub.1 is H,
--OH, --SH, --NH.sub.2, or F; R.sub.2 is (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
heterocycloalkyl, --NR.sub.10R.sub.11, or --OR.sub.10, wherein the
alkyl is substituted with one or more R.sub.8, and wherein the
aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8; each R.sub.3 is independently
at each occurrence selected from D, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.20; or two R.sub.3 together when on adjacent
carbons form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted
with one or more R.sub.20; or two R.sub.3 together when attached to
the same carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when attached to the same carbon atom form a
spiroheterocycloalkyl optionally substituted with one or more
R.sub.20; or two R.sub.3 together when on adjacent carbons form an
aryl ring optionally substituted with one or more R.sub.20; or two
R.sub.3 together when on adjacent carbons form an heteroaryl ring
optionally substituted with one or more R.sub.20; R.sub.5 and
R.sub.5' are independently H, D, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, or CN; R.sub.6 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl, halogen,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.14; R.sub.7 is H, D,
(C.sub.1-C.sub.6) alkyl, halogen, CN, NO.sub.2, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.16; or R.sub.6 and R.sub.7 together with the atoms to which
they are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16; each R.sub.8 is
independently D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted with one
or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a heterocycloalkyl ring optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form
an aryl ring optionally substituted with one or more R.sub.9; or
two R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9; each R.sub.9 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, --NH.sub.2, --OH, --C(O)R.sub.23,
--C(O)NR.sub.23R.sub.24, --NR.sub.23C(O)R.sub.24,
--NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26; R.sub.10 and
R.sub.11 are independently H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.18; or R.sub.10 and R.sub.11 together with the
nitrogen to which they are attached form a heterocycloalkyl ring
optionally substituted with one or more R.sub.18; each R.sub.14 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6)
alkyl, --NH.sub.2, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.15; each R.sub.15 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN; each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17; each R.sub.17 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.18 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.1-C.sub.6) hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19; each R.sub.19 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.20 is independently at each
occurrence (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN; each R.sub.21 and R.sub.22 is
independently H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocycloalkyl are optionally substituted with one or more
R.sub.25; each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25; each R.sub.25 is
independently at each occurrence (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN; each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN; each R.sub.27 and R.sub.28
is independently at each occurrence H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one or more substituents independently selected
from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, or di(C.sub.1-C.sub.6)
alkylamino; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, or 3; and q is
independently at each occurrence 0, 1, or 2.
13-18. (canceled)
19. The compound of claim 1, having Formula (Ii): ##STR00044## or a
pharmaceutically acceptable salt, hydrate, solvate, prodrug,
stereoisomer, and tautomer thereof, wherein: R.sub.2 is
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl is
substituted with one or more R.sub.8, and wherein the aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8; R.sub.4 is (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.12; each R.sub.8 is
independently D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted with one
or more R.sub.9; or two R.sub.8 together when on adjacent atoms
form a heterocycloalkyl ring optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form
an aryl ring optionally substituted with one or more R.sub.9; or
two R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9; each R.sub.9 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, --NH.sub.2, --OH, --C(O)R.sub.23,
--C(O)NR.sub.23R.sub.24, --NR.sub.23C(O)R.sub.24,
--NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26; R.sub.10 and
R.sub.11 are independently H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.18; or R.sub.10 and R.sub.11 together with the
nitrogen to which they are attached form a heterocycloalkyl ring
optionally substituted with one or more R.sub.18; each R.sub.12 is
independently D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --OH, --NH.sub.2, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl,
--O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13; each R.sub.13 is
independently (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or
CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.29; each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19; each R.sub.19 is independently
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; each R.sub.21 and R.sub.22 is
independently H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl
and heterocycloalkyl are optionally substituted with one or more
R.sub.25; each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25; each R.sub.25 is
independently at each occurrence (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN; each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN; each R.sub.27 and R.sub.28
is independently at each occurrence H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one or more substituents independently selected
from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, or di(C.sub.1-C.sub.6)
alkylamino; each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; and q is independently at each occurrence
0, 1, or 2.
20. The compound of claim 1 selected from the group consisting of:
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)thieno[2,3-d]pyri-
midin-4(3H)-one;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahyd-
robenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5,6,7-tetrahyd-
ro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-propylthieno[2-
,3-d]pyrimidin-4(3H)-one;
3-((4-hydroxy-1-(3-phenylpentanoyl)piperidin-4-yl)methyl)thieno[2,3-d]pyr-
imidin-4(3H)-one;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-methylthieno[2-
,3-d]pyrimidin-4(3H)-one;
6-ethyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)thieno[2,-
3-d]pyrimidin-4(3H)-one;
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6-dimethylthie-
no[2,3-d]pyrimidin-4(3H)-one;
7-(4-fluorophenyl)-3-((4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methy-
l)thieno[3,2-d]pyrimidin-4(3H)-one;
3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)thieno[3,-
2-d]pyrimidin-4(3H)-one;
(E)-4-(dimethylamino)-N-(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyri-
midin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)but-2-enamide;
and
(E)-4-(dimethylamino)-N-(4-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]-
pyrimidin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-oxobutyl)but-2-enami-
de.
21. A pharmaceutical composition comprising, a compound of claim 1,
and a pharmaceutically acceptable carrier.
22. A method of treating a disease or disorder associated with
modulation of USP7 comprising, administering to a patient in need
thereof an effective amount of a compound of claim 1, wherein the
disease or disorder associated with modulation of USP7 is selected
from cancer and metastasis, neurodegenerative diseases,
immunological disorders, diabetes, bone and joint diseases,
osteoporosis, arthritis inflammatory disorders, cardiovascular
diseases, ischemic diseases, viral infections and diseases, viral
infectivity and/or latency, and bacterial infections and
diseases.
23. (canceled)
24. A method of inhibiting USP7 comprising, administering to a
patient in need thereof an effective amount of claim 1.
25. A method of treating cancer, the method comprising
administering, to a patient in need thereof an effective amount of
claim 1, wherein the cancer is selected from liposarcoma;
neuroblastoma; glioblastoma; bladder cancer; adrenocortical cancer;
multiple myeloma; colorectal cancer; non-small cell lung cancer;
diffuse large B-cell lymphoma; Human Papilloma Virus-associated
cervical, oropharyngeal, penis, anal, thyroid or vaginal cancer;
and Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric
cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse
large B-cell lymphoma.
26. (canceled)
27. The method of claim 25, wherein the patient is selected for
treatment based on gene amplification and/or elevated tumor
expression of USP7, MDM2 or MDM4 relative to tissue-matched
expression; or based on tumor expression of wild type TP53; or
based on the tumor immune cell composition, specifically elevated
regulatory T lymphocytes, CD4+CD25+FoxP3+T cells.
28. (canceled)
29. The method of claim 25, wherein administration of the compound
induces a change in the cell cycle or cell viability.
30. The method of claim 29, wherein the change in the cell cycle or
cell viability is indicated by decreased tumor levels of MDM2
protein and/or increased levels of TP53, CDKN1A (p21, Cip1), PUMA
or BAX.
31. The method of claim 29, wherein the change in the cell cycle or
cell viability is indicated by increased expression of one or more
p53 target genes.
32. The method of claim 31, wherein the one or more p53 target
genes are CDKN1A (p21, Cip1), BBC3 (PUMA), BAX or MDM2.
33-34. (canceled)
35. A method of treating a neurodegenerative disease, the method
comprising administering to a patient in need thereof an effective
amount of a compound of claim 1, wherein the neurodegenerative
disease is selected from Alzheimer's disease, multiple sclerosis,
Huntington's disease, infectious meningitis, encephalomyelitis,
Parkinson's disease, amyotrophic lateral sclerosis, and
encephalitis.
36. (canceled)
37. A method of treating a viral infection and disease, the method
comprising administering to a patient in need thereof an effective
amount of a compound of claim 1, wherein the viral infection and
disease is selected from herpes simplex-1 or -2 viral infections,
hepatitis A, hepatitis C, SARS coronavirus infection and disease,
Epstein-Barr virus, rhinoviral infections and diseases, adenoviral
infections and diseases, and poliomvelitis.
38. (canceled)
39. A method of treating an inflammatory disease or condition, the
method comprising administering to a patient in need thereof an
effective amount of a compound of claim 1.
40. The method of claim 39, wherein the inflammatory disease or
condition is associated with a metabolic disorder selected from
Type II diabetes, insulin resistance cardiovascular disease,
arrhythmia, atherosclerosis, coronary artery disease,
hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy,
neuropathy, and macular edema; or with an inflammatory bowel
disease selected from ileitis, ulcerative colitis, Barrett's
syndrome, and Crohn's disease.
41-44. (canceled)
45. A method of inducing cell cycle arrest, apoptosis in tumor
cells, and/or enhanced tumor specific T-cell immunity, comprising
contacting the cells with an effective amount of a compound of
claim 1.
46-47. (canceled)
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of and priority to U.S.
provisional application No. 62/112,482, filed Feb. 5, 2015, the
entire contents of which are incorporated herein by reference in
its entirety.
FIELD OF DISCLOSURE
[0002] The present disclosure is directed to inhibitors of
ubiquitin-specific protease 7 (USP7) useful in the treatment of
diseases or disorders associated with USP7 enzymes. Specifically,
the disclosure is concerned with compounds and compositions
inhibiting USP7, methods of treating diseases or disorders
associated with USP7, and methods of synthesis of these
compounds.
BACKGROUND OF THE DISCLOSURE
[0003] Ubiquitination is a post translational modification
initially identified as a crucial component of proteasomal
degradation in the ubiquitin proteasome system (UPS). Chains of
Ubiquitin (Ub(s)), an 8.5 kDa highly conserved protein, are
covalently attached to substrates to be degraded in the proteasome.
(Finley D. "Recognition and processing of ubiquitin-protein
conjugates by the proteasome." Annual review of biochemistry
78:477-513, (2009)) The molecular mechanisms by which the UPS acts
are also varied, with different chain linkages of ubiquitination
controlling protein turnover, enzymatic activity, subcellular
localization, and protein-protein interactions of substrate
proteins. (Komander D., et. al. "The emerging complexity of protein
ubiquitination," Biochem. Soc. Trans. 37(Pt 5):937-53 (2009))
[0004] Ubiquitin-specific protease 7 (USP7) is a Ubiquitin Specific
Protease (USP) family deubiquitinase (DUB) that was originally
identified as an enzyme that interacted with virally-encoded
proteins of the Herpes simplex virus and later the Epstein-Barr
virus. (Everett R. D., Meredith M., Orr A., Cross A, Kathoria M.,
Parkinson J. "A novel ubiquitin-specific protease is dynamically
associated with the PML nuclear domain and binds to a herpes virus
regulatory protein," EMBO J. 16(7):1519-30 (1997); Holowaty M. N.,
Zeghouf M., Wu H., et al. "Protein profiling with Epstein-Barr
nuclear antigen-1 reveals an interaction with the
herpesvirus-associated ubiquitin-specific protease HAUSP/USP7," J.
Biol. Chem. 278(32):29987-94 (2003)) Ubiquitin Specific Proteases
(USPs) specifically cleave the isopeptide bond at the carboxy
terminus of ubiquitin. In contrast to other DUB classes, which are
thought to generally regulate ubiquitin homeostasis or to be
involved in pre-processing of linear ubiquitin chains, USPs remove
ubiquitin from specific targets. Given this substrate specificity
combined with the numerous roles ubiquitination has in the cell,
USPs are important regulators of a multitude of pathways, ranging
from preventing the proteolysis of ubquitinated substrates, to
controlling their nuclear localization.
[0005] USP7 deubiquitinates a variety of cellular targets involved
in different processes related to cancer and metastasis,
neurodegenerative diseases, immunological disorders, osteoporosis,
arthritis inflammatory disorders, cardiovascular diseases, ischemic
diseases, viral infections and diseases, and bacterial infections
and diseases.
[0006] For example, USP7 has been shown to stabilize DNMT1, a DNA
methyltransferase that maintain epigenetic silencing, to maintain
higher steady state-levels of Claspin, a protein involved in ataxia
telangiectasia and Rad3-related (ATR) phosphorylation of Chk1, and
to regulate Tip60 protein levels, a histone acetyltransferase and
transcriptional coregulator involved in adipogenesis. (Zhanwen du,
Song J., Wang Y., et al. "DNMT1 stability is regulated by proteins
coordinating deubiquitination and acetylation-driven
ubiquitination," Science Signaling 3(146) (2010); Faustrup H.,
Bekker-Jensen S., Bartek J., Lukas J., Mail N., Mailand N. "USP7
counteracts SCFbetaTrCP- but not APCCdh1-mediated proteolysis of
Claspin," The Journal of cell biology 184(1):13-9 (2009); Gao Y.,
Koppen A., Rakhsh M., et al. "Early adipogenesis is regulated
through USP7-mediated deubiquitination of the histone
acetyltransferase TIP60," Nature Communications 4:2656 (2013)
[0007] In addition to regulating the protein stability of
poly-ubiquitinated targets, USP7 also acts to control the
subcellular localization of proteins. Mono-ubiquitination of PTEN
has been shown to effect its cytoplasmic/nuclear partitioning,
where nuclear localization of PTEN is important for its tumor
suppression activity. (Trotman L. C., Wang X., Alimonti A., et al.
"Ubiquitination regulates PTEN nuclear import and tumor
suppression," Cell 128(1):141-56 (2007); Song M. S., Salmena L.,
Carracedo A., et al. "The deubiquitinylation and localization of
PTEN are regulated by a HAUSP-PML network," Nature 455(7214):813-7
(2008)) USP7 has also been shown to bind and deubiquitinate FOXO4,
a member of the FOXO subfamily of transcription factors involved in
a variety of cell processes including metabolism, cell cycle
regulation apoptosis, and response to oxidative stress, decreasing
its nuclear localization and transcriptional activity. (van der
Horst A., van der Horst O., de Vries-Smits A. M. M., et al. "FOXO4
transcriptional activity is regulated by monoubiquitination and
USP7/HAUSP," Nat. Cell Biol. 8(10):1064-73 (2006))
[0008] Cellular targets of USP7 also include the tumor suppressor
p53 and its major E3 ligase, MDM2, stabilizing p53 via the
degradation of MDM2. (Li M., Chen D., Shiloh A., et al.
"Deubiquitination of p53 by HAUSP is an important pathway for p53
stabilization," Nature 416(6881):648-53 (2002); Li M., Brooks C.
L., Kon N., Gu W. "A dynamic role of HAUSP in the p53-Mdm2
pathway," Mol. Cell. 13(6):879-86 (2004)) Structural studies have
also shown that the EBNA1 protein encoded by the Epstein-Barr virus
interacts at the same binding surface as USP7 on p53, preventing
USP7 endogenous cellular activity while recruiting USP7 to viral
promoters in order to activate latent viral gene expression.
(Saridakis V., et al. "Structure of the p53 binding domain of
HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for
EBV-mediated immortalization," Mol. Cell. 18(1):25-36 (2005);
Sarkari F., Sanchez-Alcaraz T., Wang S., Holowaty M. N., Sheng Y.,
Frappier L. "EBNA1-mediated recruitment of a histone H2B
deubiquitylating complex to the Epstein-Barr virus latent origin of
DNA replication," PLoS pathogens 5(10) (2009); Sheng Y., et al.
"Molecular recognition of p53 and MDM2 by USP7/HAUSP," Nat. Struct.
Mol. Biol. 13(3):285-91 (2006)) Similarly, the gene product of
TSPYL5, a gene frequently amplified in breast cancer and associated
with poor clinical outcome, alters the ubiquitination status of p53
via its interaction with USP7. (Epping M. T., et al. "TSPYL5
suppresses p53 levels and function by physical interaction with
USP7," Nat. Cell Biol. 13(1):102-8 (2011))
[0009] Inhibition of USP7 with small molecule inhibitors therefore
has the potential to be a treatment for cancers and other
disorders. For this reason, there remains a considerable need for
novel and potent small molecule inhibitors of USP7.
SUMMARY OF THE DISCLOSURE
[0010] A first aspect of the disclosure relates to compounds of
Formula (I):
##STR00002##
[0011] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0012] wherein:
[0013] X.sub.1 is C, S, or S(O);
[0014] X.sub.2 is
##STR00003##
[0015] R.sub.1 is H, --OH, --SH, --NH.sub.2, or F;
[0016] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0017] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0018] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0019] R.sub.4 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.12;
[0020] R.sub.5 and R.sub.5' are independently H, D,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
or CN;
[0021] R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl,
halogen, NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.14;
[0022] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16; or
[0023] R.sub.6 and R.sub.7 together with the atoms to which they
are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16;
[0024] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0025] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0026] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0027] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0028] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0029] each R.sub.12 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or
[0030] two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13;
[0031] each R.sub.13 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.29;
[0032] each R.sub.14 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.15;
[0033] each R.sub.15 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0034] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0035] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0036] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0037] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0038] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0039] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0040] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0041] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0042] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0043] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0044] each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0045] m is 0, 1, 2, 3, or 4;
[0046] n is 0, 1, 2, or 3; and
[0047] q is independently at each occurrence 0, 1, or 2.
[0048] Another aspect of the disclosure relates to a method of
treating a disease or disorder associated with modulation of USP7.
The method comprises administering to a patient in need of a
treatment for diseases or disorders associated with modulation of
USP7 an effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, hydrate, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0049] Another aspect of the disclosure is directed to a method of
inhibiting USP7. The method involves administering to a patient in
need thereof an effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, hydrate, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0050] Another aspect of the disclosure relates to a method of
treating cancer. The method comprises administering to a patient in
need thereof an effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt, hydrate, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0051] Another aspect of the disclosure relates to a method of
treating a neurodegenerative disease. The method comprises
administering to a patient in need thereof an effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
[0052] Another aspect of the disclosure relates to a method of
treating a viral infection or disease. The method comprises
administering to a patient in need thereof an effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
[0053] Another aspect of the disclosure relates to a method of
treating an inflammatory disease or condition. The method comprises
administering to a patient in need thereof an effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
[0054] Another aspect of the disclosure relates to a method of
inducing cell cycle arrest, apoptosis in tumor cells and/or
enhanced tumor-specific T-cell immunity. The method comprises
contacting the cells with an effective amount of a compound of
Formula (I), or a pharmaceutically acceptable salt, hydrate,
solvate, prodrug, stereoisomer, or tautomer thereof.
[0055] Another aspect of the disclosure is directed to
pharmaceutical compositions comprising a compound of Formula (I),
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,
stereoisomer, or tautomer thereof and a pharmaceutically acceptable
carrier. The pharmaceutical acceptable carrier may further include
an excipient, diluent, or surfactant.
[0056] Another aspect of the present disclosure relates to a
compound of Formula (I), or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for
use in the manufacture of a medicament for treating a disease
associated with inhibiting USP7.
[0057] Another aspect of the present disclosure relates to the use
of a compound of Formula (I), or a pharmaceutically acceptable
salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,
in the treatment of a disease associated with inhibiting USP7.
[0058] The present disclosure further provides methods of treating
a disease or disorder associated with modulation of USP7 including,
cancer and metastasis, neurodegenerative diseases, immunological
disorders, diabetes, bone and joint diseases, osteoporosis,
arthritis inflammatory disorders, cardiovascular diseases, ischemic
diseases, viral infections and diseases, viral infectivity and/or
latency, and bacterial infections and diseases, comprising
administering to a patient suffering from at least one of said
diseases or disorder a compound of Formula (I), or a
pharmaceutically acceptable salt, hydrate, solvate, prodrug,
stereoisomer, or tautomer thereof.
[0059] The present disclosure provides inhibitors of USP7 that are
therapeutic agents in the treatment of diseases such as cancer and
metastasis, neurodegenerative diseases, immunological disorders,
diabetes, bone and joint diseases, osteoporosis, arthritis
inflammatory disorders, cardiovascular diseases, ischemic diseases,
viral infections and diseases, viral infectivity and/or latency,
and bacterial infections and diseases.
[0060] The present disclosure further provides compounds and
compositions with an improved efficacy and safety profile relative
to known USP7 inhibitors. The present disclosure also provides
agents with novel mechanisms of action toward USP7 enzymes in the
treatment of various types of diseases including cancer and
metastasis, neurodegenerative diseases, immunological disorders,
diabetes, bone and joint diseases, osteoporosis, arthritis
inflammatory disorders, cardiovascular diseases, ischemic diseases,
viral infections and diseases, viral infectivity and/or latency,
and bacterial infections and diseases. Ultimately the present
disclosure provides the medical community with a novel
pharmacological strategy for the treatment of diseases and
disorders associated with USP7 enzymes.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0061] The present disclosure relates to compounds and compositions
that are capable of inhibiting the activity USP7. The disclosure
features methods of treating, preventing or ameliorating a disease
or disorder in which USP7 plays a role by administering to a
patient in need thereof a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt,
hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The
methods of the present disclosure can be used in the treatment of a
variety of USP7 dependent diseases and disorders by inhibiting the
activity of USP7 enzymes. Inhibition of USP7 provides a novel
approach to the treatment, prevention, or amelioration of diseases
including, but not limited to, cancer and metastasis,
neurodegenerative diseases, immunological disorders, osteoporosis,
arthritis inflammatory disorders, cardiovascular diseases, ischemic
diseases, viral infections and diseases, and bacterial infections
and diseases.
[0062] In a first aspect of the disclosure, the compounds of
Formula (I) are described:
##STR00004##
and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof, wherein R.sub.1,
R.sub.2, R.sub.3, R.sub.5, R.sub.5', X.sub.1, X.sub.2, m, and n are
as described herein above.
[0063] The details of the disclosure are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present disclosure, illustrative methods
and materials are now described. Other features, objects, and
advantages of the disclosure will be apparent from the description
and from the claims. In the specification and the appended claims,
the singular forms also include the plural unless the context
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
disclosure belongs. All patents and publications cited in this
specification are incorporated herein by reference in their
entireties.
Definitions
[0064] The articles "a" and "an" are used in this disclosure to
refer to one or more than one (e.g., to at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0065] The term "and/or" is used in this disclosure to mean either
"and" or "or" unless indicated otherwise.
[0066] The term "optionally substituted" is understood to mean that
a given chemical moiety (e.g., an alkyl group) can (but is not
required to) be bonded other substituents (e.g., heteroatoms). For
instance, an alkyl group that is optionally substituted can be a
fully saturated alkyl chain (e.g., a pure hydrocarbon).
Alternatively, the same optionally substituted alkyl group can have
sub stituents different from hydrogen. For instance, it can, at any
point along the chain be bounded to a halogen atom, a hydroxyl
group, or any other substituent described herein. Thus the term
"optionally substituted" means that a given chemical moiety has the
potential to contain other functional groups, but does not
necessarily have any further functional groups. Suitable
substituents used in the optional substitution of the described
groups include, without limitation, halogen, oxo, --OH, --CN,
--COOH, --CH.sub.2CN, --O--(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 haloalkoxy, --O--(C.sub.2-C.sub.6)
alkenyl, --O--(C.sub.2-C.sub.6) alkynyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, --OH, --OP(O)(OH).sub.2,
--OC(O)(C.sub.1-C.sub.6) alkyl, --C(O)(C.sub.1-C.sub.6) alkyl,
--OC(O)O(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --NH((C.sub.1-C.sub.6)
alkyl), --N((C.sub.1-C.sub.6) alkyl).sub.2,
--NHC(O)(C.sub.1-C.sub.6) alkyl, --C(O)NH(C.sub.1-C.sub.6) alkyl,
--S(O).sub.2(C.sub.1-C.sub.6) alkyl, --S(O)NH(C.sub.1-C.sub.6)
alkyl, and S(O)N((C.sub.1-C.sub.6) alkyl).sub.2. The substituents
can themselves be optionally substituted. "Optionally substituted"
as used herein also refers to substituted or unsubstituted whose
meaning is described below.
[0067] As used herein, the term "substituted" means that the
specified group or moiety bears one or more suitable substituents
wherein the substituents may connect to the specified group or
moiety at one or more positions. For example, an aryl substituted
with a cycloalkyl may indicate that the cycloalkyl connects to one
atom of the aryl with a bond or by fusing with the aryl and sharing
two or more common atoms.
[0068] As used herein, the term "unsubstituted" means that the
specified group bears no substituents.
[0069] Unless otherwise specifically defined, the term "aryl"
refers to cyclic, aromatic hydrocarbon groups that have 1 to 3
aromatic rings, including monocyclic or bicyclic groups such as
phenyl, biphenyl or naphthyl. Where containing two aromatic rings
(bicyclic, etc.), the aromatic rings of the aryl group may be
joined at a single point (e.g., biphenyl), or fused (e.g.,
naphthyl). The aryl group may be optionally substituted by one or
more substituents, e.g., 1 to 5 substituents, at any point of
attachment. Exemplary substituents include, but are not limited to,
--H, -halogen, --O--(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6)
alkyl, --O--(C.sub.2-C.sub.6) alkenyl, --O--(C.sub.2-C.sub.6)
alkynyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
--OH, --OP(O)(OH).sub.2, --OC(O)(C.sub.1-C.sub.6) alkyl,
--C(O)(C.sub.1-C.sub.6) alkyl, --OC(O)O(C.sub.1-C.sub.6) alkyl,
NH.sub.2, NH((C.sub.1-C.sub.6) alkyl), --N((C.sub.1-C.sub.6)
alkyl).sub.2, --S(O).sub.2--(C.sub.1-C.sub.6) alkyl,
--S(O)NH(C.sub.1-C.sub.6) alkyl, and S(O)N((C.sub.1-C.sub.6)
alkyl).sub.2. The substituents can themselves be optionally
substituted. Furthermore when containing two fused rings the aryl
groups herein defined may have an unsaturated or partially
saturated ring fused with a fully saturated ring. Exemplary ring
systems of these aryl groups include, but are not limited to,
phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,
indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl,
and the like.
[0070] Unless otherwise specifically defined, "heteroaryl" means a
monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a
polycyclic aromatic radical, containing one or more ring
heteroatoms selected from N, O, or S, the remaining ring atoms
being C. Heteroaryl as herein defined also means a bicyclic
heteroaromatic group wherein the heteroatom is selected from N, O,
or S. The aromatic radical is optionally substituted independently
with one or more substituents described herein. Examples include,
but are not limited to, furyl, thienyl, pyrrolyl, pyridyl,
pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,
benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,
benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,
imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl,
imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl,
pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,
thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl,
indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,
benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,
dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,
1,6-naphthyridinyl, benzo[de]isoquinolinyl,
pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl,
quinazolinyl, tetrazolo[1,5-a]pyridinyl,
[1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,
pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,
pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,
pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,
3,4-dihydro-2H-1.lamda..sup.2-pyrrolo[2,1-b]pyrimidine,
dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl,
furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl,
benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl,
benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine,
[1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl,
imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,
benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole,
1,3-dihydro-2H-benzo[d]imidazol-2-one,
3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,
4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,
thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,
thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof.
Furthermore when containing two fused rings the aryl groups herein
defined may have an unsaturated or partially saturated ring fused
with a fully saturated ring. Exemplary ring systems of these
heteroaryl groups include indolinyl, indolinonyl,
dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl,
thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,
3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl,
indolyl, and dihydrobenzoxanyl.
[0071] Halogen or "halo" refers to fluorine, chlorine, bromine, or
iodine.
[0072] Alkyl refers to a straight or branched chain saturated
hydrocarbon containing 1-12 carbon atoms. Examples of a
(C.sub.1-C.sub.6) alkyl group include, but are not limited to,
methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,
sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.
[0073] "Alkoxy" refers to a straight or branched chain saturated
hydrocarbon containing 1-12 carbon atoms containing a terminal "O"
in the chain, e.g., --O(alkyl). Examples of alkoxy groups include,
without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or
pentoxy groups.
[0074] "Alkenyl" refers to a straight or branched chain unsaturated
hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group
contains at least one double bond in the chain. The double bond of
an alkenyl group can be unconjugated or conjugated to another
unsaturated group. Examples of alkenyl groups include ethenyl,
propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl
group can be unsubstituted or substituted. Alkenyl, as herein
defined, may be straight or branched.
[0075] "Alkynyl" refers to a straight or branched chain unsaturated
hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group
contains at least one triple bond in the chain. Examples of alkenyl
groups include ethynyl, propargyl, n-butynyl, iso-butynyl,
pentynyl, or hexynyl. An alkynyl group can be unsubstituted or
substituted.
[0076] The term "alkylene" or "alkylenyl" refers to a divalent
alkyl radical. Any of the above mentioned monovalent alkyl groups
may be an alkylene by abstraction of a second hydrogen atom from
the alkyl. As herein defined, alkylene may also be a
C.sub.1-C.sub.6 alkylene. An alkylene may further be a
C.sub.1-C.sub.4 alkylene. Typical alkylene groups include, but are
not limited to, --CH.sub.2--, --CH(CH.sub.3)--,
--C(CH.sub.3).sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH(CH.sub.3)--, --CH.sub.2C(CH.sub.3).sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
and the like.
[0077] "Cycloalkyl" or "carbocyclyl" means monocyclic or polycyclic
saturated carbon rings containing 3-18 carbon atoms. Examples of
cycloalkyl groups include, without limitations, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,
norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or
bicyclo[2.2.2]octenyl and derivatives thereof. A C.sub.3-C.sub.8
cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon
atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged
(e.g., norbornane).
[0078] "Heterocyclyl" or "heterocycloalkyl" monocyclic or
polycyclic rings containing carbon and heteroatoms taken from
oxygen, nitrogen, or sulfur and wherein there is not delocalized
.pi. electrons (aromaticity) shared among the ring carbon or
heteroatoms. The heterocycloalkyl ring structure may be substituted
by one or more substituents. The substituents can themselves be
optionally substituted. Examples of heterocyclyl rings include, but
are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl,
tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl,
thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,
tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl
S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl,
oxazolidinonyl, and homotropanyl.
[0079] The term "hydroxyalkyl" means an alkyl group as defined
above, where the alkyl group is substituted with one or more --OH
groups. Examples of hydroxyalkyl groups include HO--CH.sub.2--,
HO--CH.sub.2--CH.sub.2-- and CH.sub.3--CH(OH)--.
[0080] The term "haloalkyl" as used herein refers to an alkyl
group, as defined herein, which is substituted one or more halogen.
Examples of haloalkyl groups include, but are not limited to,
trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl,
etc.
[0081] The term "haloalkoxy" as used herein refers to an alkoxy
group, as defined herein, which is substituted one or more halogen.
Examples of haloalkyl groups include, but are not limited to,
trifluoromethoxy, difluoromethoxy, pentafluoroethoxy,
trichloromethoxy, etc.
[0082] The term "cyano" as used herein means a substituent having a
carbon atom joined to a nitrogen atom by a triple bond, e.g.,
C.ident.N.
[0083] The term "amino" as used herein means a substituent
containing at least one nitrogen atom (e.g., NH.sub.2).
[0084] The term "alkylamino" as used herein refers to an amino or
NH.sub.2 group where one of the hydrogens has been replaced with an
alkyl group, as defined herein above, e.g., --NH(alkyl). Examples
of alkylamino groups include, but are not limited to, methylamino
(e.g., --NH(CH.sub.3)), ethylamino, propylamino, iso-propylamino,
n-butylamino, sec-butylamino, tert-butylamino, etc.
[0085] The term "dialkylamino" as used herein refers to an amino or
NH.sub.2 group where both of the hydrogens have been replaced with
alkyl groups, as defined herein above, e.g., --N(alkyl).sub.2. The
alkyl groups on the amino group can be the same or different alkyl
groups. Example of dialkylamino groups include, but are not limited
to, dimethylamino (e.g., --N(CH.sub.3).sub.2), diethylamino,
dipropylamino, diiso-propylamino, di-n-butylamino,
di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,
methyl(butylamino), etc.
[0086] "Spirocycloalkyl" or "spirocyclyl" means carbogenic bicyclic
ring systems with both rings connected through a single atom. The
ring can be different in size and nature, or identical in size and
nature. Examples include spiropentane, spirohexane, spiroheptane,
spirooctane, spirononane, or spirodecane. One or both of the rings
in a spirocycle can be fused to another ring carbocyclic,
heterocyclic, aromatic, or heteroaromatic ring. One or more of the
carbon atoms in the spirocycle can be substituted with a heteroatom
(e.g., O, N, S, or P). A (C.sub.3-C.sub.12) spirocycloalkyl is a
spirocycle containing between 3 and 12 carbon atoms. One or more of
the carbon atoms can be substituted with a heteroatom.
[0087] The term "spiroheterocycloalkyl" or "spiroheterocyclyl" is
understood to mean a spirocycle wherein at least one of the rings
is a heterocycle (e.g., at least one of the rings is furanyl,
morpholinyl, or piperadinyl).
[0088] The term "solvate" refers to a complex of variable
stoichiometry formed by a solute and solvent. Such solvents for the
purpose of the disclosure may not interfere with the biological
activity of the solute. Examples of suitable solvents include, but
are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein
water is the solvent molecule are typically referred to as
hydrates. Hydrates include compositions containing stoichiometric
amounts of water, as well as compositions containing variable
amounts of water.
[0089] The term "isomer" refers to compounds that have the same
composition and molecular weight but differ in physical and/or
chemical properties. The structural difference may be in
constitution (geometric isomers) or in the ability to rotate the
plane of polarized light (stereoisomers). With regard to
stereoisomers, the compounds of Formula (I) may have one or more
asymmetric carbon atom and may occur as racemates, racemic mixtures
and as individual enantiomers or diastereomers.
[0090] The disclosure also includes pharmaceutical compositions
comprising an effective amount of a disclosed compound and a
pharmaceutically acceptable carrier. Representative
"pharmaceutically acceptable salts" include, e.g., water-soluble
and water-insoluble salts, such as the acetate, amsonate
(4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate,
bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate,
calcium, calcium edetate, camsylate, carbonate, chloride, citrate,
clavulariate, dihydrochloride, edetate, edisylate, estolate,
esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate,
glycollylarsanilate, hexafluorophosphate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, magnesium,
malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate,
pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate),
pantothenate, phosphate/diphosphate, picrate, polygalacturonate,
propionate, p-toluenesulfonate, salicylate, stearate, subacetate,
succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate salts.
[0091] A "patient" or "subject" is a mammal, e.g., a human, mouse,
rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate,
such as a monkey, chimpanzee, baboon or rhesus.
[0092] An "effective amount" when used in connection with a
compound is an amount effective for treating or preventing a
disease in a subject as described herein.
[0093] The term "carrier", as used in this disclosure, encompasses
carriers, excipients, and diluents and means a material,
composition or vehicle, such as a liquid or solid filler, diluent,
excipient, solvent or encapsulating material, involved in carrying
or transporting a pharmaceutical agent from one organ, or portion
of the body, to another organ, or portion of the body of a
subject.
[0094] The term "treating" with regard to a subject, refers to
improving at least one symptom of the subject's disorder. Treating
includes curing, improving, or at least partially ameliorating the
disorder.
[0095] The term "disorder" is used in this disclosure to mean, and
is used interchangeably with, the terms disease, condition, or
illness, unless otherwise indicated.
[0096] The term "administer", "administering", or "administration"
as used in this disclosure refers to either directly administering
a disclosed compound or pharmaceutically acceptable salt of the
disclosed compound or a composition to a subject, or administering
a prodrug derivative or analog of the compound or pharmaceutically
acceptable salt of the compound or composition to the subject,
which can form an equivalent amount of active compound within the
subject's body.
[0097] The term "prodrug," as used in this disclosure, means a
compound which is convertible in vivo by metabolic means (e.g., by
hydrolysis) to a disclosed compound.
[0098] The present disclosure relates to compounds or
pharmaceutically acceptable salts, hydrates, solvates, prodrugs,
stereoisomers, or tautomers thereof, capable of inhibiting USP7,
which are useful for the treatment of diseases and disorders
associated with modulation of a USP7 enzyme. The disclosure further
relates to compounds, or pharmaceutically acceptable salts,
hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof,
which are useful for inhibiting USP7.
[0099] In one embodiment, the compounds of Formula (I) have the
structure of Formula (Ia):
##STR00005##
[0100] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0101] wherein:
[0102] X.sub.1 is C, S, or S(O);
[0103] R.sub.1 is H, --OH, --SH, --NH.sub.2, or F;
[0104] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0105] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0106] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0107] R.sub.4 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.12;
[0108] R.sub.5 and R.sub.5' are independently H, D,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
or CN;
[0109] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16;
[0110] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0111] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0112] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0113] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0114] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0115] each R.sub.12 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or
[0116] two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13;
[0117] each R.sub.13 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.29;
[0118] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0119] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0120] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0121] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0122] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0123] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0124] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0125] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0126] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0127] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0128] each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0129] m is 0, 1, 2, 3, or 4;
[0130] n is 0, 1, 2, or 3; and
[0131] q is independently at each occurrence 0, 1, or 2.
[0132] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Ib):
##STR00006##
[0133] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0134] wherein:
[0135] X.sub.1 is C, S, or S(O);
[0136] R.sub.1 is H, --OH, --SH, --NH.sub.2, or F;
[0137] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0138] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0139] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0140] R.sub.5 and R.sub.5' are independently H, D,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
or CN;
[0141] R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl,
halogen, NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.14;
[0142] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16; or
[0143] R.sub.6 and R.sub.7 together with the atoms to which they
are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16;
[0144] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0145] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0146] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0147] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0148] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0149] each R.sub.14 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.15;
[0150] each R.sub.15 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0151] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0152] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0153] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0154] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0155] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0156] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0157] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0158] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0159] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0160] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0161] m is 0, 1, 2, 3, or 4;
[0162] n is 0, 1, 2, or 3; and
[0163] q is independently at each occurrence 0, 1, or 2.
[0164] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Ic):
##STR00007##
[0165] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0166] wherein:
[0167] X.sub.1 is C, S, or S(O);
[0168] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0169] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0170] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0171] R.sub.4 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.12;
[0172] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16;
[0173] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0174] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0175] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0176] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0177] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0178] each R.sub.12 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or
[0179] two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13;
[0180] each R.sub.13 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.29;
[0181] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0182] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0183] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0184] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0185] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0186] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0187] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0188] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0189] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0190] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0191] each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0192] m is 0, 1, 2, 3, or 4;
[0193] n is 0, 1, 2, or 3; and
[0194] q is independently at each occurrence 0, 1, or 2.
[0195] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Id):
##STR00008##
[0196] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0197] wherein:
[0198] X.sub.1 is C, S, or S(O);
[0199] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0200] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0201] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0202] R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl,
halogen, NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.14;
[0203] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16; or
[0204] R.sub.6 and R.sub.7 together with the atoms to which they
are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16;
[0205] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0206] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0207] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0208] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0209] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0210] each R.sub.14 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.15;
[0211] each R.sub.15 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0212] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0213] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0214] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0215] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0216] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0217] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0218] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0219] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0220] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0221] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0222] m is 0, 1, 2, 3, or 4;
[0223] n is 0, 1, 2, or 3; and
[0224] q is independently at each occurrence 0, 1, or 2.
[0225] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Ie):
##STR00009##
[0226] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0227] wherein:
[0228] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0229] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0230] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0231] R.sub.4 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.12;
[0232] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16;
[0233] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0234] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0235] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0236] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0237] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0238] each R.sub.12 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or
[0239] two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13;
[0240] each R.sub.13 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.29;
[0241] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0242] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0243] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0244] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0245] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0246] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0247] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0248] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0249] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0250] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0251] each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0252] m is 0, 1, 2, 3, or 4;
[0253] n is 0, 1, 2, or 3; and
[0254] q is independently at each occurrence 0, 1, or 2.
[0255] In another embodiment, the compounds of Formula (I) have the
structure of Formula (If):
##STR00010##
[0256] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0257] wherein:
[0258] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0259] each R.sub.3 is independently at each occurrence selected
from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20; or
[0260] two R.sub.3 together when on adjacent carbons form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.20; or two R.sub.3 together when attached to the same
carbon atom form a (C.sub.3-C.sub.8) spirocycloalkyl optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20; or two R.sub.3
together when on adjacent carbons form an aryl ring optionally
substituted with one or more R.sub.20; or two R.sub.3 together when
on adjacent carbons form an heteroaryl ring optionally substituted
with one or more R.sub.20;
[0261] R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl,
halogen, NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.14;
[0262] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16; or
[0263] R.sub.6 and R.sub.7 together with the atoms to which they
are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16;
[0264] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0265] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0266] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0267] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0268] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0269] each R.sub.14 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.15;
[0270] each R.sub.15 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0271] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0272] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0273] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0274] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0275] each R.sub.20 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN;
[0276] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0277] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0278] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0279] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0280] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0281] m is 0, 1, 2, 3, or 4;
[0282] n is 0, 1, 2, or 3; and
[0283] q is independently at each occurrence 0, 1, or 2.
[0284] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Ig):
##STR00011##
[0285] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0286] wherein:
[0287] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0288] R.sub.4 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.12;
[0289] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16;
[0290] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0291] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0292] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0293] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0294] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0295] each R.sub.12 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or
[0296] two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13;
[0297] each R.sub.13 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.29;
[0298] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0299] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0300] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0301] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0302] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0303] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0304] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0305] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0306] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0307] each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; and
[0308] q is independently at each occurrence 0, 1, or 2.
[0309] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Ih):
##STR00012##
[0310] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0311] wherein:
[0312] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0313] R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6)
alkenyl, (C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl,
halogen, NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.14;
[0314] R.sub.7 is H, D, (C.sub.1-C.sub.6) alkyl, halogen, CN,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.16; or
[0315] R.sub.6 and R.sub.7 together with the atoms to which they
are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one or more R.sub.16;
[0316] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0317] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0318] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0319] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0320] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0321] each R.sub.14 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.15;
[0322] each R.sub.15 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0323] each R.sub.16 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.17;
[0324] each R.sub.17 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0325] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0326] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0327] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0328] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0329] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0330] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0331] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino; and
[0332] q is independently at each occurrence 0, 1, or 2.
[0333] In another embodiment, the compounds of Formula (I) have the
structure of Formula (Ii):
##STR00013##
[0334] and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, and tautomers thereof,
[0335] wherein:
[0336] R.sub.2 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl,
--NR.sub.10R.sub.11, or --OR.sub.10, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.8;
[0337] R.sub.4 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.12;
[0338] each R.sub.8 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN,
--(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.21,
--CO(O)R.sub.21, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9; or
[0339] two R.sub.8 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.9; or two R.sub.8 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.9; or two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9; or two
R.sub.8 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.9;
[0340] each R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26;
[0341] R.sub.10 and R.sub.11 are independently H, (C.sub.1-C.sub.6)
alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.18; or
[0342] R.sub.10 and R.sub.11 together with the nitrogen to which
they are attached form a heterocycloalkyl ring optionally
substituted with one or more R.sub.18;
[0343] each R.sub.12 is independently D, (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13; or
[0344] two R.sub.12 together when on adjacent atoms form a
(C.sub.3-C.sub.8) cycloalkyl optionally substituted with one or
more R.sub.13; or two R.sub.12 together when on adjacent atoms form
a heterocycloalkyl ring optionally substituted with one or more
R.sub.13; or two R.sub.12 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.13; or two
R.sub.12 together when on adjacent atoms form an heteroaryl ring
optionally substituted with one or more R.sub.13;
[0345] each R.sub.13 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.0-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.29;
[0346] each R.sub.18 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.1-C.sub.6)
hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19;
[0347] each R.sub.19 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino, --OH,
or CN;
[0348] each R.sub.21 and R.sub.22 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25;
[0349] each R.sub.23 and R.sub.24 is independently H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25;
[0350] each R.sub.25 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN;
[0351] each R.sub.26 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN;
[0352] each R.sub.27 and R.sub.28 is independently at each
occurrence H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino;
[0353] each R.sub.29 is independently at each occurrence
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN; and
[0354] q is independently at each occurrence 0, 1, or 2.
[0355] In some embodiments of the Formulae above, X.sub.1 is C. In
another embodiment, X.sub.1 is S. In yet another embodiment,
X.sub.1 is S(O).
[0356] In some embodiments of the Formulae above, X.sub.2 is
##STR00014##
In another embodiment, X.sub.2 is
##STR00015##
[0357] In some embodiments of the Formulae above, R.sub.1 is H,
--OH, --SH, --NH.sub.2, or F. In another embodiment, R.sub.1 is H,
--OH, or F. In yet another embodiment, R.sub.1 is --OH, or F. In
another embodiment, R.sub.1 is --OH.
[0358] In some embodiments of the Formulae above, R.sub.2 is
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl, or
NR.sub.10R.sub.11, wherein the alkyl, aryl, heteroaryl, cycloalkyl
and heterocycloalkyl are optionally substituted with one or more
R.sub.8. In another embodiment, R.sub.2 is (C.sub.1-C.sub.4) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
heterocycloalkyl, or NR.sub.10R.sub.11, wherein the alkyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one or more R.sub.8. In yet another embodiment,
R.sub.2 is (C.sub.1-C.sub.4) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, heterocycloalkyl, or
NR.sub.10R.sub.11, wherein the alkyl, aryl, heteroaryl, cycloalkyl
and heterocycloalkyl are optionally substituted with one to three
R.sub.8. In another embodiment, R.sub.2 is (C.sub.1-C.sub.4) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, or NR.sub.10R.sub.11, wherein
the alkyl, aryl, or heteroaryl are optionally substituted with one
to three R.sub.8. In yet another embodiment, R.sub.2 is
(C.sub.1-C.sub.4) alkyl, (C.sub.6-C.sub.14) aryl, or
NR.sub.10R.sub.11, wherein the alkyl and aryl are optionally
substituted with one to three R.sub.8.
[0359] In some embodiments of the Formulae above, R.sub.3 is
selected from D, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.20. In another embodiment, R.sub.3 is selected from D or
(C.sub.1-C.sub.6) alkyl, optionally substituted with one or more
R.sub.20. In yet another embodiment, R.sub.3 is selected from D or
(C.sub.1-C.sub.6) alkyl, optionally substituted with one to three
R.sub.20. In another embodiment, R.sub.3 is selected from D or
(C.sub.1-C.sub.4) alkyl, optionally substituted with one to three
R.sub.20.
[0360] In another embodiment, two R.sub.3 together when on adjacent
carbons form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted
with one or more R.sub.20. In another embodiment, two R.sub.3
together when attached to the same carbon atom form a
(C.sub.3-C.sub.8) spirocycloalkyl optionally substituted with one
or more R.sub.20. In another embodiment, two R.sub.3 together when
attached to the same carbon atom form a spiroheterocycloalkyl
optionally substituted with one or more R.sub.20. In another
embodiment, two R.sub.3 together when on adjacent carbons form an
aryl ring optionally substituted with one or more R.sub.20. In
another embodiment, two R.sub.3 together when on adjacent carbons
form an heteroaryl ring optionally substituted with one or more
R.sub.20.
[0361] In some embodiments of the Formulae above, R.sub.4 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.12. In another
embodiment, R.sub.4 is (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14)
aryl, or heteroaryl wherein the alkyl, aryl, and heteroaryl are
optionally substituted with one or more R.sub.12. In another
embodiment, R.sub.4 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.12.
[0362] In some embodiments of the Formulae above, R.sub.5 is H, D,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
or CN. In another embodiment, R.sub.5 is H, D, (C.sub.1-C.sub.6)
alkyl, (C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, or halogen. In yet another
embodiment, R.sub.5 is H, D, (C.sub.1-C.sub.3) alkyl,
(C.sub.1-C.sub.3) alkoxy, (C.sub.1-C.sub.3) haloalkyl,
(C.sub.1-C.sub.3) haloalkoxy, or halogen. In another embodiment,
R.sub.5 is H, D, (C.sub.1-C.sub.3) alkyl, or halogen. In yet
another embodiment, R.sub.5 is H, D, methyl, ethyl, propyl,
iso-propyl, or halogen.
[0363] In some embodiments of the Formulae above, R.sub.5' is H, D,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
or CN. In another embodiment, R.sub.5' is H, D, (C.sub.1-C.sub.6)
alkyl, (C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, or halogen. In yet another
embodiment, R.sub.5' is H, D, (C.sub.1-C.sub.3) alkyl,
(C.sub.1-C.sub.3) alkoxy, (C.sub.1-C.sub.3) haloalkyl,
(C.sub.1-C.sub.3) haloalkoxy, or halogen. In another embodiment,
R.sub.5' is H, D, (C.sub.1-C.sub.3) alkyl, or halogen. In yet
another embodiment, R.sub.5' is H, D, methyl, ethyl, propyl,
iso-propyl, or halogen.
[0364] In some embodiments of the Formulae above, R.sub.6 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl, halogen,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one or more R.sub.14. In another embodiment,
R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.1-C.sub.6) haloalkyl, halogen,
NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, or heterocycloalkyl, wherein the alkyl, aryl,
heteroaryl, cycloalkyl, and heterocycloalkyl are optionally
substituted with one to three R.sub.14. In yet another embodiment,
R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, or
heteroaryl, wherein the alkyl, aryl, and heteroaryl are optionally
substituted with one to three R.sub.14. In another embodiment,
R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl,
wherein the alkyl and aryl are optionally substituted with one to
three R.sub.14.
[0365] In some embodiments of the Formulae above, R.sub.7 is H, D,
(C.sub.1-C.sub.6) alkyl, halogen, CN, NO.sub.2, (C.sub.6-C.sub.14)
aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or
heterocycloalkyl, wherein the alkyl, aryl, heteroaryl, cycloalkyl,
and heterocycloalkyl are optionally substituted with one or more
R.sub.16. In another embodiment, R.sub.7 is H, D, (C.sub.1-C.sub.6)
alkyl, halogen, CN, NO.sub.2, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one to three R.sub.16. In yet another
embodiment, R.sub.7 is H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.16. In another embodiment, R.sub.7 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, or heteroaryl,
wherein the alkyl, aryl, and heteroaryl are optionally substituted
with one to three R.sub.16. In yet another embodiment, R.sub.7 is
H, (C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl, wherein the
alkyl, and aryl are optionally substituted with one to three
R.sub.16.
[0366] In another embodiment, R.sub.6 and R.sub.7 together with the
atoms to which they are attached form a (C.sub.3-C.sub.8)cycloalkyl
optionally substituted with one or more R.sub.16. In yet another
embodiment, R.sub.6 and R.sub.7 together with the atoms to which
they are attached form a (C.sub.3-C.sub.8)cycloalkyl optionally
substituted with one to three R.sub.16.
[0367] In some embodiments of the Formulae above, each R.sub.8 is
D, (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.19,
--CO(O)R.sub.19, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.9. In another embodiment, each R.sub.8 is D,
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --(C.sub.1-C.sub.3)-alkylene-O--(C.sub.1-C.sub.6) alkyl,
--(C.sub.0-C.sub.4)-alkylene-aryl,
--(C.sub.0-C.sub.4)-alkylene-heteroaryl, (C.sub.3-C.sub.10)
cycloalkyl, heterocycloalkyl, --(C.sub.0-C.sub.4)-alkylene-O-aryl,
--(C.sub.0-C.sub.4)-alkylene-O-heteroaryl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --S-heteroaryl, --C(O)R.sub.19,
--CO(O)R.sub.19, --C(O)NR.sub.21R.sub.22, --S(O).sub.qR.sub.21,
--S(O).sub.qNR.sub.21R.sub.22, --NR.sub.21S(O).sub.qR.sub.22,
--(C.sub.0-C.sub.3)-alkylene-NR.sub.21R.sub.22,
--NR.sub.21C(O)R.sub.22, --NR.sub.21C(O)C(O)R.sub.22,
--NR.sub.21C(O)NR.sub.21R.sub.22, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, --SF.sub.5, or
--OR.sub.21, wherein the alkyl, alkylene, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.9.
[0368] In another embodiment, two R.sub.8 together when on adjacent
atoms form a (C.sub.3-C.sub.8) cycloalkyl optionally substituted
with one or more R.sub.9. In yet another embodiment, two R.sub.8
together when on adjacent atoms form a heterocycloalkyl ring
optionally substituted with one or more R.sub.9. In another
embodiment, two R.sub.8 together when on adjacent atoms form an
aryl ring optionally substituted with one or more R.sub.9. In yet
another embodiment, two R.sub.8 together when on adjacent atoms
form an heteroaryl ring optionally substituted with one or more
R.sub.9.
[0369] In some embodiments of the Formulae above, R.sub.9 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14)
aryl, heteroaryl, --NH.sub.2, --OH, --C(O)R.sub.23,
--C(O)NR.sub.23R.sub.24, --NR.sub.23C(O)R.sub.24,
--NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.26. In another
embodiment, R.sub.9 is independently (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
--NH.sub.2, --OH, --C(O)R.sub.23, --C(O)NR.sub.23R.sub.24,
--NR.sub.23C(O)R.sub.24, --NR.sub.23R.sub.24, --S(O).sub.qR.sub.23,
--S(O).sub.qNR.sub.23R.sub.24, --NR.sub.23S(O).sub.qR.sub.24, oxo,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --O-aryl, CN, or --O-heteroaryl, wherein
the alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one to three R.sub.26.
[0370] In some embodiments of the Formulae above, R.sub.10 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.18. In another
embodiment, R.sub.10 is H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.18.
[0371] In some embodiments of the Formulae above, R.sub.11 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one or more R.sub.18. In another
embodiment, R.sub.11 is H, (C.sub.1-C.sub.6) alkyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.18.
[0372] In another embodiment, R.sub.10 and R.sub.11 together with
the nitrogen to which they are attached form a heterocycloalkyl
ring optionally substituted with one or more R.sub.18. In yet
another embodiment, R.sub.10 and R.sub.11 together with the
nitrogen to which they are attached form a heterocycloalkyl ring
optionally substituted with one to three R.sub.18.
[0373] In some embodiments of the Formulae above, R.sub.12 is D,
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --OH, --NH.sub.2, --C(O)(C.sub.1-C.sub.6) alkyl,
--S(O).sub.q(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.3-C.sub.8) cycloalkyl, heterocycloalkyl,
--O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13. In another embodiment, R.sub.12 is D, (C.sub.1-C.sub.6)
alkyl, (C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --OH, --NH.sub.2,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --C(O)O(C.sub.1-C.sub.6) alkyl,
--C(O)NR.sub.27R.sub.28, --S(O).sub.qNR.sub.27R.sub.28,
--NR.sub.27R.sub.28, --NR.sub.27C(O)NR.sub.27R.sub.28,
--NR.sub.27C(O)OR.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--NR.sub.27C(O)R.sub.28, halogen, --P(O)((C.sub.1-C.sub.6)
alkyl).sub.2, --P(O)(aryl).sub.2, --SiMe.sub.3, or --SF.sub.5,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.13.
[0374] In another embodiment, two R.sub.12 together when on
adjacent atoms form a (C.sub.3-C.sub.8) cycloalkyl optionally
substituted with one or more R.sub.13. In yet another embodiment,
two R.sub.12 together when on adjacent atoms form a
heterocycloalkyl ring optionally substituted with one or more
R.sub.13. In another embodiment, two R.sub.12 together when on
adjacent atoms form an aryl ring optionally substituted with one or
more R.sub.13. In yet another embodiment, two R.sub.12 together
when on adjacent atoms form an heteroaryl ring optionally
substituted with one or more R.sub.13.
[0375] In some embodiments of the Formulae above, R.sub.13 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, (C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8)
cycloalkyl, heterocycloalkyl, --O-aryl, --O-heteroaryl,
--O-heterocycloalkyl, --O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or
CN, wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.29. In another embodiment, R.sub.13 is (C.sub.1-C.sub.4)
alkyl, (C.sub.1-C.sub.4) alkoxy, (C.sub.1-C.sub.4) haloalkyl,
(C.sub.1-C.sub.4) haloalkoxy, halogen, --C(O)(C.sub.1-C.sub.4)
alkyl, --S(O).sub.q(C.sub.1-C.sub.4) alkyl, --NH.sub.2,
(C.sub.1-C.sub.4) alkylamino, di(C.sub.1-C.sub.4) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.3-C.sub.8) cycloalkyl,
heterocycloalkyl, --O-aryl, --O-heteroaryl, --O-heterocycloalkyl,
--O--(C.sub.3-C.sub.8)cycloalkyl, --OH, or CN, wherein in the
alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are
optionally substituted with one to three R.sub.29.
[0376] In some embodiments of the Formulae above, R.sub.14 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6)
alkyl, --NH.sub.2, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.15. In another embodiment, R.sub.14 is (C.sub.1-C.sub.6)
alkyl, (C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.15. In yet another embodiment, R.sub.14 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
CN, --C(O)(C.sub.1-C.sub.4) alkyl, --S(O).sub.q(C.sub.1-C.sub.4)
alkyl, --NH.sub.2, (C.sub.1-C.sub.4) alkylamino,
di(C.sub.1-C.sub.4) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one to three
R.sub.15.
[0377] In some embodiments of the Formulae above, R.sub.15 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN. In another embodiment, R.sub.15 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.4) alkyl, --S(O).sub.q(C.sub.1-C.sub.4) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.4)
alkylamino, --OH, or CN.
[0378] In some embodiments of the Formulae above, R.sub.16 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
CN, --C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6)
alkyl, --NH.sub.2, --OH, (C.sub.1-C.sub.6) alkylamino,
di(C.sub.1-C.sub.6) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one or more
R.sub.17. In another embodiment, R.sub.16 is (C.sub.1-C.sub.6)
alkyl, (C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, halogen, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2, --OH,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.17. In yet another embodiment, R.sub.16 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
CN, --C(O)(C.sub.1-C.sub.4) alkyl, --S(O).sub.q(C.sub.1-C.sub.4)
alkyl, --NH.sub.2, --OH, (C.sub.1-C.sub.4) alkylamino,
di(C.sub.1-C.sub.4) alkylamino, (C.sub.6-C.sub.14) aryl,
heteroaryl, (C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl,
wherein in the alkyl, aryl, heteroaryl, cycloalkyl, and
heterocycloalkyl are optionally substituted with one to three
R.sub.17.
[0379] In some embodiments of the Formulae above, R.sub.17 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN. In another embodiment, R.sub.17 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.4) alkyl, --S(O).sub.q(C.sub.1-C.sub.4) alkyl,
--NH.sub.2, (C.sub.1-C.sub.4) alkylamino, di(C.sub.1-C.sub.4)
alkylamino, --OH, or CN.
[0380] In some embodiments of the Formulae above, R.sub.18 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.1-C.sub.6) hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one or more R.sub.19. In another embodiment, R.sub.18 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
(C.sub.1-C.sub.6) hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.6)
alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl, --NH.sub.2,
(C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.19. In yet another embodiment, R.sub.18 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
(C.sub.1-C.sub.4) hydroxyalkyl, --OH, CN, --C(O)(C.sub.1-C.sub.4)
alkyl, --S(O).sub.q(C.sub.1-C.sub.4) alkyl, --NH.sub.2,
(C.sub.1-C.sub.4) alkylamino, di(C.sub.1-C.sub.4) alkylamino,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein in the alkyl, aryl, heteroaryl,
cycloalkyl, and heterocycloalkyl are optionally substituted with
one to three R.sub.19.
[0381] In some embodiments of the Formulae above, R.sub.19 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN. In another embodiment, R.sub.19 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.4) alkyl, --S(O).sub.q(C.sub.1-C.sub.4) alkyl,
--NH.sub.2, (C.sub.1-C.sub.4) alkylamino, di(C.sub.1-C.sub.4)
alkylamino, --OH, or CN.
[0382] In some embodiments of the Formulae above, R.sub.20 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN. In another embodiment, R.sub.20 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--OH, --NH.sub.2, or CN.
[0383] In some embodiments of the Formulae above, R.sub.21 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25. In another embodiment, R.sub.21 is H, (C.sub.1-C.sub.6)
alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one to three R.sub.25.
[0384] In some embodiments of the Formulae above, R.sub.22 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
R.sub.25. In another embodiment, R.sub.22 is H, (C.sub.1-C.sub.6)
alkyl, (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one to three R.sub.25.
[0385] In some embodiments of the Formulae above, R.sub.23 is H,
(C.sub.1-C.sub.6) alkyl,
[0386] (C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl and heterocycloalkyl are optionally substituted with one
or more R.sub.25. In another embodiment, R.sub.23 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one to three R.sub.25.
[0387] In some embodiments of the Formulae above, R.sub.24 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl are
optionally substituted with one or more R.sub.25. In another
embodiment, R.sub.24 is H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, aryl, heteroaryl,
cycloalkyl and heterocycloalkyl are optionally substituted with one
to three R.sub.25.
[0388] In some embodiments of the Formulae above, R.sub.25 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN. In another embodiment, R.sub.25 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN.
[0389] In some embodiments of the Formulae above, R.sub.26 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.6) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN. In another embodiment,
R.sub.26 is (C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--NR.sub.27C(O)R.sub.28, --NR.sub.27S(O).sub.qR.sub.28,
--C(O)R.sub.27, --C(O)NR.sub.27R.sub.28, --NR.sub.27R.sub.28,
--S(O).sub.qR.sub.27, --S(O).sub.qNR.sub.27R.sub.28,
--P(O)((C.sub.1-C.sub.4) alkyl).sub.2, --P(O)(aryl).sub.2,
--SiMe.sub.3, --SF.sub.5, --OH, or CN.
[0390] In some embodiments of the Formulae above, R.sub.27 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino. In another
embodiment, R.sub.27 is H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one to three substituents independently selected
from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, or di(C.sub.1-C.sub.6)
alkylamino.
[0391] In some embodiments of the Formulae above, R.sub.28 is H,
(C.sub.1-C.sub.6) alkyl, (C.sub.2-C.sub.6) alkenyl,
(C.sub.2-C.sub.6) alkynyl, (C.sub.6-C.sub.14) aryl, heteroaryl,
(C.sub.5-C.sub.8) cycloalkyl, or heterocycloalkyl, wherein the
alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and
heterocycloalkyl are optionally substituted with one or more
substituents independently selected from (C.sub.1-C.sub.6) alkyl,
(C.sub.1-C.sub.6) alkoxy, (C.sub.1-C.sub.6) haloalkyl,
(C.sub.1-C.sub.6) haloalkoxy, --NH.sub.2, (C.sub.1-C.sub.6)
alkylamino, or di(C.sub.1-C.sub.6) alkylamino. In another
embodiment, R.sub.28 is H, (C.sub.1-C.sub.6) alkyl,
(C.sub.2-C.sub.6) alkenyl, (C.sub.2-C.sub.6) alkynyl,
(C.sub.6-C.sub.14) aryl, heteroaryl, (C.sub.5-C.sub.8) cycloalkyl,
or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl and heterocycloalkyl are optionally
substituted with one to three substituents independently selected
from (C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, or di(C.sub.1-C.sub.6)
alkylamino.
[0392] In some embodiments, of the Formulae above, R.sub.29 is
(C.sub.1-C.sub.6) alkyl, (C.sub.1-C.sub.6) alkoxy,
(C.sub.1-C.sub.6) haloalkyl, (C.sub.1-C.sub.6) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.6) alkyl, --S(O).sub.q(C.sub.1-C.sub.6) alkyl,
--NH.sub.2, (C.sub.1-C.sub.6) alkylamino, di(C.sub.1-C.sub.6)
alkylamino, --OH, or CN. In another embodiment, R.sub.29 is
(C.sub.1-C.sub.4) alkyl, (C.sub.1-C.sub.4) alkoxy,
(C.sub.1-C.sub.4) haloalkyl, (C.sub.1-C.sub.4) haloalkoxy, halogen,
--C(O)(C.sub.1-C.sub.4) alkyl, --S(O).sub.q(C.sub.1-C.sub.4) alkyl,
--NH.sub.2, (C.sub.1-C.sub.4) alkylamino, di(C.sub.1-C.sub.4)
alkylamino, --OH, or CN.
[0393] In some embodiments of the Formulae above, m is 0, 1, 2, 3,
or 4. In another embodiment, m is 0, 1, 2, or 3. In yet another
embodiment, m is 0, 1, or 2. In another embodiment, m is 0 or 1. In
yet another embodiment, m is 0. In another embodiment, m is 1. In
yet another embodiment, m is 2. In yet another embodiment, m is 3.
In yet another embodiment, m is 4.
[0394] In some embodiments of the Formulae above, n is 0, 1, 2, or
3. In another embodiment, n is 0, 1, or 2. In yet another
embodiment, n is 0 or 1. In another embodiment, n is 0. In yet
another embodiment, n is 1. In another embodiment, n is 2. In yet
another embodiment, n is 3.
[0395] In some embodiments of the Formulae above, q is 0, 1, or 2.
In another embodiment, q is 0. In yet another embodiment, q is 1.
In another embodiment, q is 2.
[0396] In some embodiments of the Formulae above, X.sub.1 is C.
[0397] In some embodiments of the Formulae above, R.sub.1 is
--OH.
[0398] In some embodiments of the Formulae above, R.sub.4 is
(C.sub.6-C.sub.14) aryl or heteroaryl.
[0399] In some embodiments of the Formulae above, R.sub.5 is H.
[0400] In some embodiments of the Formulae above, R.sub.5' is
H.
[0401] In some embodiments of the Formulae above, R.sub.6 is H,
(C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl.
[0402] In some embodiments of the Formulae above, R.sub.7 is H,
(C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl.
[0403] In some embodiments of the Formulae above, R.sub.6 and
R.sub.7 together with the atoms to which they are attached form a
(C.sub.3-C.sub.8)cycloalkyl optionally substituted with one or more
R.sub.16.
[0404] In some embodiments of the Formulae above, n is 1.
[0405] In some embodiments of the Formulae above, X.sub.1 is C. In
another embodiment, X.sub.1 is C and X.sub.2 is
##STR00016##
In yet another embodiment, X.sub.1 is C, X.sub.2 is
##STR00017##
and R.sub.1 is OH. In another embodiment, X.sub.1 is C, X.sub.2
is
##STR00018##
R.sub.1 is OH and R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8. In yet another embodiment,
X.sub.1 is C, X.sub.2 is
##STR00019##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, and R.sub.4 is
(C.sub.1-C.sub.6) alkyl or (C.sub.6-C.sub.14) aryl, wherein the
alkyl and aryl are optionally substituted with one or more
R.sub.12. In another embodiment, X.sub.1 is C, X.sub.2 is
##STR00020##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.4 is (C.sub.1-C.sub.6)
alkyl or (C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are
optionally substituted with one or more R.sub.12, and R.sub.5 is H.
In yet another embodiment, X.sub.1 is C, X.sub.2 is
##STR00021##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.4 is (C.sub.1-C.sub.6)
alkyl or (C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are
optionally substituted with one or more R.sub.12, R.sub.5 is H, and
R.sub.5' is H. In another embodiment, X.sub.1 is C, X.sub.2 is
##STR00022##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.4 is (C.sub.1-C.sub.6)
alkyl or (C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are
optionally substituted with one or more R.sub.12, R.sub.5 is H,
R.sub.5' is H, and R.sub.7 is H, (C.sub.1-C.sub.6) alkyl, or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.16. In yet another embodiment,
X.sub.1 is C, X.sub.2 is
##STR00023##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.4 is (C.sub.1-C.sub.6)
alkyl or (C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are
optionally substituted with one or more R.sub.12, R.sub.5 is H,
R.sub.5' is H, R.sub.7 is H, (C.sub.1-C.sub.6) alkyl, or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.16, and n is 1.
[0406] In some embodiments of the Formulae above, X.sub.1 is C. In
another embodiment, X.sub.1 is C and X.sub.2 is
##STR00024##
In yet another embodiment, X.sub.1 is C, X.sub.2 is
##STR00025##
and R.sub.1 is OH. In another embodiment, X.sub.1 is C, X.sub.2
is
##STR00026##
R.sub.1 is OH and R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8. In yet another embodiment,
X.sub.1 is C, X.sub.2 is
##STR00027##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, and R.sub.5 is H. In another
embodiment, X.sub.1 is C, X.sub.2 is
##STR00028##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.5 is H, and R.sub.5' is
H. In yet another embodiment, X.sub.1 is C, X.sub.2 is
##STR00029##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.5 is H, R.sub.5' is H,
and R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14)
aryl, wherein the alkyl and aryl are optionally substituted with
one or more R.sub.14. In another embodiment, X.sub.1 is C, X.sub.2
is
##STR00030##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.5 is H, R.sub.5' is H,
R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl,
wherein the alkyl and aryl are optionally substituted with one or
more R.sub.14, and R.sub.7 is H, (C.sub.1-C.sub.6) alkyl, or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.16. In yet another embodiment,
X.sub.1 is C, X.sub.2 is
##STR00031##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.5 is H, R.sub.5' is H,
R.sub.6 is H, (C.sub.1-C.sub.6) alkyl, or (C.sub.6-C.sub.14) aryl,
wherein the alkyl and aryl are optionally substituted with one or
more R.sub.14, R.sub.7 is H, (C.sub.1-C.sub.6) alkyl, or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.16, and n is 1. In another
embodiment, X.sub.1 is C, X.sub.2 is
##STR00032##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.5 is H, R.sub.5' is H,
and R.sub.6 and R.sub.7 together with the atoms to which they are
attached form a (C.sub.3-C.sub.8)cycloalkyl optionally substituted
with one or more R.sub.16. In yet another embodiment, X.sub.1 is C,
X.sub.2 is
##STR00033##
R.sub.1 is OH, R.sub.2 is (C.sub.1-C.sub.6) alkyl or
(C.sub.6-C.sub.14) aryl, wherein the alkyl and aryl are optionally
substituted with one or more R.sub.8, R.sub.5 is H, R.sub.5' is H,
R.sub.6 and R.sub.7 together with the atoms to which they are
attached form a (C.sub.3-C.sub.8)cycloalkyl optionally substituted
with one or more R.sub.16, and n is 1.
[0407] Non-limiting illustrative compounds of the disclosure
include: [0408]
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)thieno[2,3-
-d]pyrimidin-4(3H)-one (I-1); [0409]
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6,7,8-tetrahyd-
robenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one (I-2); [0410]
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-3,5,6,7-tetrahyd-
ro-4H-cyclopenta[4,5]thieno[2,3-d]pyrimidin-4-one (I-3); [0411]
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-propylthieno[2-
,3-d]pyrimidin-4(3H)-one (I-4); [0412]
3-((4-hydroxy-1-(3-phenylpentanoyl)piperidin-4-yl)methyl)thieno[2,3-d]pyr-
imidin-4(3H)-one (I-5); [0413]
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-methylthieno[2-
,3-d]pyrimidin-4(3H)-one (I-6); [0414]
6-ethyl-3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)thieno[2,-
3-d]pyrimidin-4(3H)-one (I-7); [0415]
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-5,6-dimethylthie-
no[2,3-d]pyrimidin-4(3H)-one (I-8); [0416]
7-(4-fluorophenyl)-3-((4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methy-
l)thieno[3,2-d]pyrimidin-4(3H)-one (I-9); [0417]
3-((1-benzoyl-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluorophenyl)thieno[3,-
2-d]pyrimidin-4(3H)-one (I-10); [0418]
(E)-4-(dimethylamino)-N-(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyri-
midin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)but-2-enamide
(I-11); and [0419]
(E)-4-(dimethylamino)-N-(4-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyri-
midin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-4-oxobutyl)but-2-enamide
(I-12).
[0420] In another embodiment of the disclosure, the compounds of
Formula (I) are enantiomers. In some embodiments the compounds are
the (S)-enantiomer. In other embodiments the compounds are the
(R)-enantiomer. In yet other embodiments, the compounds of Formula
(I) may be (+) or (-) enantiomers.
[0421] It should be understood that all isomeric forms are included
within the present disclosure, including mixtures thereof. If the
compound contains a double bond, the sub stituent may be in the E
or Z configuration. If the compound contains a disubstituted
cycloalkyl, the cycloalkyl substituent may have a cis- or trans
configuration. All tautomeric forms are also intended to be
included.
[0422] Compounds of the disclosure, and pharmaceutically acceptable
salts, hydrates, solvates, stereoisomers and prodrugs thereof may
exist in their tautomeric form (for example, as an amide or imino
ether). All such tautomeric forms are contemplated herein as part
of the present disclosure.
[0423] The compounds of the disclosure may contain asymmetric or
chiral centers, and, therefore, exist in different stereoisomeric
forms. It is intended that all stereoisomeric forms of the
compounds of the disclosure as well as mixtures thereof, including
racemic mixtures, form part of the present disclosure. In addition,
the present disclosure embraces all geometric and positional
isomers. For example, if a compound of the disclosure incorporates
a double bond or a fused ring, both the cis- and trans-forms, as
well as mixtures, are embraced within the scope of the disclosure.
Each compound herein disclosed includes all the enantiomers that
conform to the general structure of the compound. The compounds may
be in a racemic or enantiomerically pure form, or any other form in
terms of stereochemistry. The assay results may reflect the data
collected for the racemic form, the enantiomerically pure form, or
any other form in terms of stereochemistry.
[0424] Diastereomeric mixtures can be separated into their
individual diastereomers on the basis of their physical chemical
differences by methods well known to those skilled in the art, such
as, for example, by chromatography and/or fractional
crystallization. Enantiomers can be separated by converting the
enantiomeric mixture into a diastereomeric mixture by reaction with
an appropriate optically active compound (e.g., chiral auxiliary
such as a chiral alcohol or Mosher's acid chloride), separating the
diastereomers and converting (e.g., hydrolyzing) the individual
diastereomers to the corresponding pure enantiomers. Also, some of
the compounds of the disclosure may be atropisomers (e.g.,
substituted biaryls) and are considered as part of this disclosure.
Enantiomers can also be separated by use of a chiral HPLC
column.
[0425] It is also possible that the compounds of the disclosure may
exist in different tautomeric forms, and all such forms are
embraced within the scope of the disclosure. Also, for example, all
keto-enol and imine-enamine forms of the compounds are included in
the disclosure.
[0426] All stereoisomers (for example, geometric isomers, optical
isomers and the like) of the present compounds (including those of
the salts, solvates, esters and prodrugs of the compounds as well
as the salts, solvates and esters of the prodrugs), such as those
which may exist due to asymmetric carbons on various substituents,
including enantiomeric forms (which may exist even in the absence
of asymmetric carbons), rotameric forms, atropisomers, and
diastereomeric forms, are contemplated within the scope of this
disclosure, as are positional isomers (such as, for example,
4-pyridyl and 3-pyridyl). (For example, if a compound of Formula
(I) incorporates a double bond or a fused ring, both the cis- and
trans-forms, as well as mixtures, are embraced within the scope of
the disclosure. Also, for example, all keto-enol and imine-enamine
forms of the compounds are included in the disclosure.) Individual
stereoisomers of the compounds of the disclosure may, for example,
be substantially free of other isomers, or may be admixed, for
example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present disclosure can
have the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate", "ester,"
"prodrug" and the like, is intended to equally apply to the salt,
solvate, ester and prodrug of enantiomers, stereoisomers, rotamers,
tautomers, positional isomers, racemates or prodrugs of the
inventive compounds.
[0427] The compounds of Formula I may form salts which are also
within the scope of this disclosure. Reference to a compound of the
Formula herein is understood to include reference to salts thereof,
unless otherwise indicated.
[0428] The present disclosure relates to compounds which are
modulators of USP7. In one embodiment, the compounds of the present
disclosure are inhibitors of USP7.
[0429] The disclosure is directed to compounds as described herein
and pharmaceutically acceptable salts, hydrates, solvates,
prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical
compositions comprising one or more compounds as described herein,
or pharmaceutically acceptable salts, hydrates, solvates, prodrugs,
stereoisomers, or tautomers thereof.
Method of Synthesizing the Compounds
[0430] The compounds of the present disclosure may be made by a
variety of methods, including standard chemistry. Suitable
synthetic routes are depicted in the Schemes given below.
[0431] The compounds of Formula (I) may be prepared by methods
known in the art of organic synthesis as set forth in part by the
following synthetic schemes. In the schemes described below, it is
well understood that protecting groups for sensitive or reactive
groups are employed where necessary in accordance with general
principles or chemistry. Protecting groups are manipulated
according to standard methods of organic synthesis (T. W. Greene
and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third
edition, Wiley, New York 1999). These groups are removed at a
convenient stage of the compound synthesis using methods that are
readily apparent to those skilled in the art. The selection
processes, as well as the reaction conditions and order of their
execution, shall be consistent with the preparation of compounds of
Formula (I).
[0432] Those skilled in the art will recognize if a stereocenter
exists in the compounds of Formula (I). Accordingly, the present
disclosure includes both possible stereoisomers (unless specified
in the synthesis) and includes not only racemic compounds but the
individual enantiomers and/or diastereomers as well. When a
compound is desired as a single enantiomer or diastereomer, it may
be obtained by stereospecific synthesis or by resolution of the
final product or any convenient intermediate. Resolution of the
final product, an intermediate, or a starting material may be
affected by any suitable method known in the art. See, for example,
"Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen,
and L. N. Mander (Wiley-Interscience, 1994).
[0433] The compounds described herein may be made from commercially
available starting materials or synthesized using known organic,
inorganic, and/or enzymatic processes.
Preparation of Compounds
[0434] The compounds of the present disclosure can be prepared in a
number of ways well known to those skilled in the art of organic
synthesis. By way of example, compounds of the present disclosure
can be synthesized using the methods described below, together with
synthetic methods known in the art of synthetic organic chemistry,
or variations thereon as appreciated by those skilled in the art.
Preferred methods include but are not limited to those methods
described below. Compounds of the present disclosure can be
synthesized by following the steps outlined in General Schemes 1
and 2 which comprise different sequences of assembling
intermediates Ia-Ij. Starting materials are either commercially
available or made by known procedures in the reported literature or
as illustrated.
##STR00034##
[0435] wherein R.sub.2-R.sub.3, R.sub.5', R.sub.5', R.sub.6,
R.sub.7, X.sub.1, m, and n are defined as in Formula (I).
[0436] The general way of preparing compounds of Formula (I) by
using intermediates Ia, Ib, Ic, and Id is outlined in General
Scheme 1. Alkylation of Ia with Ib using a base, e.g., cesium
carbonate, in a solvent, e.g., dimethylformamide (DMF), at elevated
temperature yields Ic. Deprotection of intermediate Ic using a
strong acid such as trifluoroacetic acid (TFA) in a solvent, e.g.,
dichloromethane (DCM) yields Id. Acylation of intermediate Id to
produce a compound of Formula (I) where X.sub.1 is C can be
accomplished by coupling of an acid under standard coupling
conditions using a coupling reagent, e.g.,
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), or
O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate
(HBTU), and a base, e.g., triethylamine or
N,N-diisopropylethylamine (DIPEA), in a solvent, e.g.,
dichloromethane or DMF to provide compounds of Formula (I).
Alternatively, intermediate Id can be acylated with an acid
chloride or carbamoyl chloride using a base, e.g., triethylamine or
DIPEA, and in a solvent, e.g., dichloromethane, to produce a
compound of Formula (I) where X.sub.1 is C. For synthesis of
compounds of Formula (I) where X.sub.1 is S or S(O), intermediate
Id is treated with a sulfonyl chloride or a sulfinic chloride and a
base, e.g., triethylamine or N,N-diisopropylethylamine (DIPEA), in
a solvent, e.g., dichloromethane, DMF to provide the desired
product of Formula (I).
##STR00035##
[0437] wherein R.sub.2-R.sub.5, R.sub.5', R.sub.7, X.sub.1, m, and
n are defined as in Formula (I).
[0438] Alternatively, molecules of Formula I can be prepared using
intermediates Ie, If, Ig, Ih, Ii, and Ij as outlined in General
Scheme 2. Reaction of intermediate Ie with sodium methoxide in
solvent, e.g., 1,4-dioxane, provides intermediate If. Coupling of
If with an arylboronic acid or heteroarylboronic acid using a
catalytic amount of a palladium catalyst, e.g.,
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butyl ether, and a
base, e.g., cesium carbonate, in a solvent, e.g., 1,4-dioxane, at
elevated temperature provides Ig. Intermediate Ih is then prepared
by treatment of Ig with a strong acid, e.g., hydrochloric acid, in
a solvent, e.g., 1,4-dioxane, at an elevated temperature.
Alkylation of Ih with Ib using a base, e.g., cesium carbonate, in a
solvent, e.g., dimethylformamide (DMF), yields Ii. Deprotection of
intermediate Ii using a strong acid such as hydrochloric acid (HCl)
in a solvent, e.g., 1,4-dioxane yields Ij. Acylation of
intermediate Ij to produce a compound of Formula (I) where X.sub.1
is C can be accomplished by coupling of an acid under standard
coupling conditions using a coupling reagent, e.g.,
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HATU), or
O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate
(HBTU), and a base, e.g., triethylamine or
N,N-diisopropylethylamine (DIPEA), in a solvent, e.g.,
dichloromethane or DMF to provide compounds of Formula (I).
Alternatively, intermediate Ij can be acylated with an acid
chloride or carbamoyl chloride using a base, e.g., triethylamine or
DIPEA, and in a solvent, e.g., dichloromethane, to produce a
compound of Formula (I) where X.sub.1 is C. For synthesis of
compounds of Formula I where X.sub.1 is S or S(O), intermediate Ij
is treated with a sulfonyl chloride or a sulfinic chloride and a
base, e.g., triethylamine or N,N-diisopropylethylamine (DIPEA), in
a solvent, e.g., dichloromethane, DMF to provide the desired
product of Formula (I).
[0439] A mixture of enantiomers, diastereomers, cis/trans isomers
resulting from the process described above can be separated into
their single components by chiral salt technique, chromatography
using normal phase, reverse phase or chiral column, depending on
the nature of the separation.
[0440] It should be understood that in the description and formula
shown above, the various groups R.sub.2-R.sub.7, X.sub.1, m, n, and
other variables are as defined above, except where otherwise
indicated. Furthermore, for synthetic purposes, the compounds of
General Schemes 1 and 2 are mere representative with elected
radicals to illustrate the general synthetic methodology of the
compounds of Formula (I) as defined herein.
Methods of Using the Disclosed Compounds
[0441] Another aspect of the disclosure relates to a method of
treating a disease or disorder associated with modulation of USP7.
The method comprises administering to a patient in need of a
treatment for diseases or disorders associated with modulation of
USP7 an effective amount the compositions and compounds of Formula
(I).
[0442] In another aspect, the present disclosure is directed to a
method of inhibiting USP7. The method involves administering to a
patient in need thereof an effective amount of a compound of
Formula (I).
[0443] Another aspect of the present disclosure relates to a method
of treating, preventing, inhibiting or eliminating a disease or
disorder in a patient associated with the inhibition of USP7, the
method comprising administering to a patient in need thereof an
effective amount of a compound of Formula (I). In one embodiment,
the disease or disorder is selected from the group consisting of
cancer and metastasis, neurodegenerative diseases, immunological
disorders, diabetes, bone and joint diseases, osteoporosis,
arthritis inflammatory disorders, cardiovascular diseases, ischemic
diseases, viral infections and diseases, viral infectivity and/or
latency, and bacterial infections and diseases.
[0444] The present disclosure also relates to the use of an
inhibitor of USP7 for the preparation of a medicament used in the
treatment, prevention, inhibition or elimination of a disease or
condition mediated by USP7, wherein the medicament comprises a
compound of Formula (I).
[0445] In another aspect, the present disclosure relates to a
method for the manufacture of a medicament for treating,
preventing, inhibiting, or eliminating a disease or condition
mediated by USP7, wherein the medicament comprises a compound of
Formula (I).
[0446] Another aspect of the present disclosure relates to a
compound of Formula (I) for use in the manufacture of a medicament
for treating a disease associated with inhibiting USP7.
[0447] In another aspect, the present disclosure relates to the use
of a compound of Formula (I) in the treatment of a disease
associated with inhibiting USP7.
[0448] Another aspect of the disclosure relates to a method of
treating cancer. The method comprises administering to a patient in
need thereof an effective amount of a compound of Formula (I).
[0449] In another aspect, the present disclosure relates to a
method of treating a neurodegenerative disease. The method
comprises administering to a patient in need thereof an effective
amount of a compound of Formula (I).
[0450] Another aspect of the disclosure relates to a method of
treating a viral infection and disease. The method comprises
administering to a patient in need thereof an effective amount of a
compound of Formula (I).
[0451] In another aspect, the present disclosure relates to a
method of treating an inflammatory disease or condition. The method
comprises administering to a patient in need thereof an effective
amount of a compound of Formula (I).
[0452] Another aspect of the disclosure relates to a method of
inducing cell cycle arrest, apoptosis in tumor cells, and/or
enhanced tumor-specific T cell immunity. The method comprises
contacting the cells with an effective amount of a compound of
Formula (I).
[0453] In one embodiment, the present disclosure relates to the use
of an inhibitor of USP7 for the preparation of a medicament used in
treatment, prevention, inhibition or elimination of a disease or
disorder associated with associated with cancer and metastasis,
neurodegenerative diseases, immunological disorders, diabetes, bone
and joint diseases, osteoporosis, arthritis inflammatory disorders,
cardiovascular diseases, ischemic diseases, viral infections and
diseases, viral infectivity and/or latency, and bacterial
infections and diseases.
[0454] In another embodiment, the present disclosure relates to a
compound of Formula (I) or a pharmaceutical composition comprising
a compound of the present disclosure and a pharmaceutically
acceptable carrier used for the treatment of cancers including, but
not limited to, liposarcoma, neuroblastoma, glioblastoma, bladder
cancer, adrenocortical cancer, multiple myeloma, colorectal cancer,
non-small cell lung cancer, Human Papilloma Virus-associated
cervical, oropharyngeal, penis, anal, thyroid or vaginal cancer or
Epstein-Barr Virus-associated nasopharyngeal carcinoma, gastric
cancer, rectal cancer, thyroid cancer, Hodgkin lymphoma or diffuse
large B-cell lymphoma.
[0455] In some embodiments, the patient is selected for treatment
based on gene amplification and/or elevated tumor expression of
USP7, MDM2 or MDM4 relative to tissue-matched expression. In other
embodiments, the patient is selected for the treatment based on
tumor expression of wild type TP53 or based on the tumor immune
cell composition, specifically elevated regulatory T lymphocytes,
CD4+CD25+FoxP3+T cells.
[0456] In some embodiments, administration of a compound of Formula
(I) or a pharmaceutical composition comprising a compound of the
present disclosure and a pharmaceutically acceptable carrier
induces a change in the cell cycle or cell viability.
[0457] For example, the change in the cell cycle or cell viability
may be indicated by decreased tumor levels of MDM2 protein and/or
increased levels of TP53, CDKN1A (p21, Cip1), PUMA or BAX or by
increased expression of one or more p53 target genes. In one
embodiment, the p53 target genes include, but are not limited to,
CDKN1A (p21, Cip1), BBC3 (PUMA), BAX or MDM2.
[0458] In another embodiment, the present disclosure relates to a
compound of Formula (I) or a pharmaceutical composition comprising
a compound of the present disclosure and a pharmaceutically
acceptable carrier used for the treatment of neurodegenerative
diseases including, but not limited to, Alzheimer's disease,
multiple sclerosis, Huntington's disease, infectious meningitis,
encephalomyelitis, Parkinson's disease, amyotrophic lateral
sclerosis, or encephalitis.
[0459] Another embodiment of the present disclosure relates to a
compound of Formula (I) or a pharmaceutical composition comprising
a compound of the present disclosure and a pharmaceutically
acceptable carrier used for the treatment of viral infections and
diseases including but not limited to, herpes simplex-1 or -2 viral
infections, hepatitis A, hepatitis C, SARS coronavirus infection
and disease, Epstein-Barr virus, rhinoviral infections and
diseases, adenoviral infections and diseases, or poliomyelitis.
[0460] In another embodiment, the present disclosure relates to a
compound of Formula (I) or a pharmaceutical composition comprising
a compound of the present disclosure and a pharmaceutically
acceptable carrier used for the treatment of inflammatory diseases
or conditions is associated with metabolic disorders including, but
not limited to, Type II diabetes, insulin resistance cardiovascular
disease, arrhythmia, atherosclerosis, coronary artery disease,
hypertriglyceridemia, dyslipidemia, retinopathy, nephropathy,
neuropathy, or macular edema.
[0461] In another embodiment, the present disclosure relates to a
compound of Formula (I) or a pharmaceutical composition comprising
a compound of the present disclosure and a pharmaceutically
acceptable carrier used for the treatment of inflammatory diseases
or conditions is associated with inflammatory bowel diseases
including, but not limited to, ileitis, ulcerative colitis,
Barrett's syndrome, or Crohn's disease
[0462] Another aspect of the disclosure is directed to
pharmaceutical compositions comprising a compound of Formula (I)
and a pharmaceutically acceptable carrier. The pharmaceutical
acceptable carrier may further include an excipient, diluent, or
surfactant.
[0463] In one embodiment, are provided methods of treating a
disease or disorder associated with modulation of USP7 including,
cancer and metastasis, neurodegenerative diseases, immunological
disorders, diabetes, bone and joint diseases, osteoporosis,
arthritis inflammatory disorders, cardiovascular diseases, ischemic
diseases, viral infections and diseases, viral infectivity and/or
latency, and bacterial infections and diseases, comprising
administering to a patient suffering from at least one of said
diseases or disorder a compound of Formula (I).
[0464] One therapeutic use of the compounds or compositions of the
present disclosure which inhibit USP7 is to provide treatment to
patients or subjects suffering from cancer and metastasis,
neurodegenerative diseases, immunological disorders, diabetes, bone
and joint diseases, osteoporosis, arthritis inflammatory disorders,
cardiovascular diseases, ischemic diseases, viral infections and
diseases, viral infectivity and/or latency, and bacterial
infections and diseases.
[0465] The disclosed compounds of the disclosure can be
administered in effective amounts to treat or prevent a disorder
and/or prevent the development thereof in subjects.
[0466] Administration of the disclosed compounds can be
accomplished via any mode of administration for therapeutic agents.
These modes include systemic or local administration such as oral,
nasal, parenteral, transdermal, subcutaneous, vaginal, buccal,
rectal or topical administration modes.
[0467] Depending on the intended mode of administration, the
disclosed compositions can be in solid, semi-solid or liquid dosage
form, such as, for example, injectables, tablets, suppositories,
pills, time-release capsules, elixirs, tinctures, emulsions,
syrups, powders, liquids, suspensions, or the like, sometimes in
unit dosages and consistent with conventional pharmaceutical
practices. Likewise, they can also be administered in intravenous
(both bolus and infusion), intraperitoneal, subcutaneous or
intramuscular form, and all using forms well known to those skilled
in the pharmaceutical arts.
[0468] Illustrative pharmaceutical compositions are tablets and
gelatin capsules comprising a Compound of the Disclosure and a
pharmaceutically acceptable carrier, such as a) a diluent, e.g.,
purified water, triglyceride oils, such as hydrogenated or
partially hydrogenated vegetable oil, or mixtures thereof, corn
oil, olive oil, sunflower oil, safflower oil, fish oils, such as
EPA or DHA, or their esters or triglycerides or mixtures thereof,
omega-3 fatty acids or derivatives thereof, lactose, dextrose,
sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose
and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid,
its magnesium or calcium salt, sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, sodium acetate, sodium
chloride and/or polyethylene glycol; for tablets also; c) a binder,
e.g., magnesium aluminum silicate, starch paste, gelatin,
tragacanth, methylcellulose, sodium carboxymethylcellulose,
magnesium carbonate, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, waxes and/or
polyvinylpyrrolidone, if desired; d) a disintegrant, e.g.,
starches, agar, methyl cellulose, bentonite, xanthan gum, algic
acid or its sodium salt, or effervescent mixtures; e) absorbent,
colorant, flavorant and sweetener; f) an emulsifier or dispersing
agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,
labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12,
captex 355, gelucire, vitamin E TGPS or other acceptable
emulsifier; and/or g) an agent that enhances absorption of the
compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400,
PEG200.
[0469] Liquid, particularly injectable, compositions can, for
example, be prepared by dissolution, dispersion, etc. For example,
the disclosed compound is dissolved in or mixed with a
pharmaceutically acceptable solvent such as, for example, water,
saline, aqueous dextrose, glycerol, ethanol, and the like, to
thereby form an injectable isotonic solution or suspension.
Proteins such as albumin, chylomicron particles, or serum proteins
can be used to solubilize the disclosed compounds.
[0470] The disclosed compounds can be also formulated as a
suppository that can be prepared from fatty emulsions or
suspensions; using polyalkylene glycols such as propylene glycol,
as the carrier.
[0471] The disclosed compounds can also be administered in the form
of liposome delivery systems, such as small unilamellar vesicles,
large unilamellar vesicles and multilamellar vesicles. Liposomes
can be formed from a variety of phospholipids, containing
cholesterol, stearylamine or phosphatidylcholines. In some
embodiments, a film of lipid components is hydrated with an aqueous
solution of drug to a form lipid layer encapsulating the drug, as
described in U.S. Pat. No. 5,262,564 which is hereby incorporated
by reference in its entirety.
[0472] Disclosed compounds can also be delivered by the use of
monoclonal antibodies as individual carriers to which the disclosed
compounds are coupled. The disclosed compounds can also be coupled
with soluble polymers as targetable drug carriers. Such polymers
can include polyvinylpyrrolidone, pyran copolymer,
polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine
substituted with palmitoyl residues. Furthermore, the Disclosed
compounds can be coupled to a class of biodegradable polymers
useful in achieving controlled release of a drug, for example,
polylactic acid, polyepsilon caprolactone, polyhydroxy butyric
acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels. In one embodiment, disclosed compounds are not
covalently bound to a polymer, e.g., a polycarboxylic acid polymer,
or a polyacrylate.
[0473] Parental injectable administration is generally used for
subcutaneous, intramuscular or intravenous injections and
infusions. Injectables can be prepared in conventional forms,
either as liquid solutions or suspensions or solid forms suitable
for dissolving in liquid prior to injection.
[0474] Another aspect of the disclosure is directed to
pharmaceutical compositions comprising a compound of Formula (I)
and a pharmaceutically acceptable carrier. The pharmaceutical
acceptable carrier may further include an excipient, diluent, or
surfactant.
[0475] Compositions can be prepared according to conventional
mixing, granulating or coating methods, respectively, and the
present pharmaceutical compositions can contain from about 0.1% to
about 99%, from about 5% to about 90%, or from about 1% to about
20% of the disclosed compound by weight or volume.
[0476] The dosage regimen utilizing the disclosed compound is
selected in accordance with a variety of factors including type,
species, age, weight, sex and medical condition of the patient; the
severity of the condition to be treated; the route of
administration; the renal or hepatic function of the patient; and
the particular disclosed compound employed. A physician or
veterinarian of ordinary skill in the art can readily determine and
prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0477] Effective dosage amounts of the disclosed compounds, when
used for the indicated effects, range from about 0.5 mg to about
5000 mg of the disclosed compound as needed to treat the condition.
Compositions for in vivo or in vitro use can contain about 0.5, 5,
20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or
5000 mg of the disclosed compound, or, in a range of from one
amount to another amount in the list of doses. In one embodiment,
the compositions are in the form of a tablet that can be
scored.
EXAMPLES
[0478] The disclosure is further illustrated by the following
examples and synthesis schemes, which are not to be construed as
limiting this disclosure in scope or spirit to the specific
procedures herein described. It is to be understood that the
examples are provided to illustrate certain embodiments and that no
limitation to the scope of the disclosure is intended thereby. It
is to be further understood that resort may be had to various other
embodiments, modifications, and equivalents thereof which may
suggest themselves to those skilled in the art without departing
from the spirit of the present disclosure and/or scope of the
appended claims.
Analytical Methods, Materials, and Instrumentation
[0479] Unless otherwise noted, reagents and solvents were used as
received from commercial suppliers. Proton nuclear magnetic
resonance (NMR) spectra were obtained on either Bruker or Varian
spectrometers at 300 or 400 MHz. Spectra are given in ppm (.delta.)
and coupling constants, J, are reported in Hertz. Tetramethylsilane
(TMS) was used as an internal standard. Mass spectra were collected
using a Waters ZQ Single Quad Mass Spectrometer (ion trap
electrospray ionization (ESI)). Purity and low resolution mass
spectral data were measured using Waters Acquity i-class
ultra-performance liquid chromatography (UPLC) system with Acquity
Photo Diode Array Detector, Acquity Evaporative Light Scattering
Detector (ELSD) and Waters ZQ Mass Spectrometer. Data was acquired
using Waters MassLynx 4.1 software and purity characterized by UV
wavelength 220 nm, evaporative light scattering detection (ELSD)
and electrospray positive ion (ESI). (Column: Acquity UPLC BEH C18
1.7 .mu.m 2.1.times.50 mm; Flow rate 0.6 mL/min; Solvent A
(95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/Formic Acid),
Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid); gradient:
5-100% B from 0 to 2 mins, hold 100% B to 2.2 mins and 5% B at 2.21
mins. Preparatory HPLC purifications were conducted on a Waters
SunFire C18 OBD Prep Column, 100 .ANG., 5 .mu.m, 19 mm.times.50 mm,
Waters XBridge BEH C18 OBD Prep Column, 130 .ANG., 5 .mu.m, 19
mm.times.50 mm with UV detection (Waters 2489 UV/998 PDA), Waters
SunFire C18 OBD Prep Column, 100 .ANG., 5 .mu.m, 19 mm.times.150
mm, Waters XBridge BEH Shield RP18 OBD Prep Column, 130 .ANG., 5
.mu.m, 19 mm.times.150 mm, or Waters XSelect CSH C18 OBD Prep
Column, 130 .ANG., 5 .mu.m, 19 mm.times.150 mm at 254 nm or 220 nm
using a standard solvent gradient program (or as designated
below).
[0480] Abbreviations used in the following examples and elsewhere
herein are: [0481] atm atmosphere [0482] br broad [0483] DIPEA
N,N-diisopropylethylamine [0484] DMA N,N-dimethylacetamide [0485]
DMF N,N-dimethylformamide [0486] DMSO dimethyl sulfoxide [0487] EI
electron ionization [0488] ESI electrospray ionization [0489] Et
ethyl [0490] GCMS gas chromatography-mass spectrometry [0491] h
hour(s) [0492] HATU
2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0493] HPLC high-performance liquid
chromatography [0494] LCMS liquid chromatography-mass spectrometry
[0495] m multiplet [0496] Me methyl [0497] MHz megahertz [0498] min
minutes [0499] MS molecular sieves [0500] MW microwave [0501] NMR
nuclear magnetic resonance [0502] ppm parts per million [0503] s
singlet [0504] TFA trifluoroacetic acid [0505] TLC thin layer
chromatography [0506] v volume [0507] wt weight
Example 1
Intermediate 2-1.
7-(4-Fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)thieno[3,2-d]pyrimi-
din-4(3H)-one hydrochloric acid salt
##STR00036##
[0508] Step 1. 7-bromo-4-methoxythieno[3,2-d]pyrimidine
[0509] To a suspension of sodium methoxide (2.71 g, 50.1 mmol) in
1,4-dioxane (20 ml) under nitrogen was added
7-bromo-4-chlorothieno[3,2-d]pyrimidine (2.50 g, 10.0 mmol) in one
portion. The resulting mixture was stirred at room temperature for
12 h then concentrated under reduced pressure. The residue was
diluted with water (100 mL) and extracted with ethyl acetate
(2.times.100 mL). The combined organic layers were first washed
with water (75 mL) and saturated aqueous sodium chloride (75 mL),
then dried over anhydrous magnesium sulfate, filtered and
concentrated under reduced pressure to afford
7-bromo-4-methoxythieno[3,2-d]pyrimidine (2.30 g, 94%), which was
used without further purification. LCMS: (ESI) m/z 244.85, 246.89
[M+H].
Step 2. 7-(4-Fluorophenyl)-4-methoxythieno[3,2-d]pyrimidine
[0510] In a 5 mL vial was added
7-bromo-4-methoxythieno[3,2-d]pyrimidine (Step 1, 350 mg, 1.43
mmol), (4-fluorophenyl)boronic acid (300 mg, 2.14 mmol), and
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butyl ether (52 mg,
0.071 mmol) in 1,4-dioxane followed by cesium carbonate (1.40 g,
4.28 mmol). The resulting mixture was heated in a sealed tube for
16 h at 100.degree. C., then cooled to room temperature and diluted
with dichloromethane (150 mL). The mixture was then washed with
saturated aqueous ammonium chloride (50 mL) and saturated aqueous
brine (50 mL). The organic layer dried over anhydrous magnesium
sulfate, filtered and concentrated under reduced pressure. The
residue was purified by column chromatography (0 to 25% ethyl
acetate/hexanes) to afford
7-(4-fluorophenyl)-4-methoxythieno[3,2-d]pyrimidine (271 mg, 73%).
LCMS: (ESI) m/z 261.04 [M+H].
Step 3. 7-(4-Fluorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one
[0511] In a 100-mL round-bottom flask was added hydrogen chloride
(12.0 M aqueous, 1.74 ml, 20.8 mmol) and
7-(4-fluorophenyl)-4-methoxythieno[3,2-d]pyrimidine (Step 2, 0.271
g, 1.041 mmol) in 1,4-dioxane (1.7 mL) to give a white suspension.
The reaction mixture was heated at 70.degree. C. for 1 h, then
cooled to room temperature, diluted with water (25 mL) and
filtered. The filtrate was washed with water (1 mL) and hexane (1
mL), then concentrated under reduced pressure to afford
7-(4-fluorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one (207 mg, 81%),
which was used without further purification. LCMS: (ESI) m/z 246.96
[M+H].
Step 4. tert-Butyl
4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-hyd-
roxypiperidine-1-carboxylate
[0512] To a 100-mL round-bottom flask was added
7-(4-fluorophenyl)thieno[3,2-d]pyrimidin-4(3H)-one (Step 3, 100 mg,
0.403 mmol), tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate
(86 mg, 0.403 mmol), and cesium carbonate (394 mg, 1.21 mmol) in
DMF (2.01 mL). The reaction mixture was heated at 80.degree. C. for
18 h then cooled to room temperature. The reaction mixture was
diluted with ethyl acetate (150 mL) and washed with saturated
aqueous ammonium chloride (50 mL) and saturated aqueous sodium
bicarbonate (50 mL). The organic layer was dried over anhydrous
magnesium sulfate, filtered and concentrated under reduced pressure
to afford tert-butyl
4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-hyd-
roxypiperidine-1-carboxylate (139 mg, 75%), which was used without
further purification. LCMS: (ESI) m/z 459.95 [M+H].
Step 5.
7-(4-Fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)thieno[3,2-d-
]pyrimidin-4(3H)-one hydrochloric acid salt
[0513] To a 50-mL round-bottom flask was added tert-butyl
4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-hyd-
roxypiperidine-1-carboxylate (Step 4, 116 mg, 0.251 mmol) and
hydrochloric acid (4.0 M in 1,4-dioxane, 0.838 mL, 0.251 mmol). The
resulting mixture was stirred for 2 h at room temperature, then
concentrated under reduced pressure to afford
7-(4-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)thieno[3,2-d]pyrimi-
din-4(3H)-one hydrochloric acid salt (Intermediate 2-1, 100 mg,
100%), which was used without further purification. LCMS: (ESI) m/z
359.99 [M+H].
Methods for the Synthesis of Compounds of Formula (I)
Method A
Example 2
7-(4-Fluorophenyl)-3-((4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methyl-
)thieno[3,2-d]pyrimidin-4(3H)-one (I-9)
##STR00037##
[0515] In a 10-mL vial was added
7-(4-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)thieno[3,2-d]pyrimi-
din-4(3H)-one hydrochloric acid salt (Intermediate 2-1, 33 mg,
0.091 mmol), 4-methoxybenzoic acid (17 mg, 0.110 mmol), HATU (0.038
g, 0.100 mmol), DMF (0.913 ml) and triethylamine (0.051 ml, 0.365
mmol). The reaction mixture was stirred for 8 h and then diluted
with ethyl acetate (100 mL). The organic layer was washed with
saturated aqueous ammonium chloride (25 mL) and saturated aqueous
sodium bicarbonate (25 mL), then dried over anhydrous magnesium
sulfate. The solids were filtered and the solvent removed under
reduced pressure. The residue was purified by column chromatography
(75 to 100% ethyl acetate/hexanes) to afford
7-(4-fluorophenyl)-3-((4-hydroxy-1-(4-methoxybenzoyl)piperidin-4-yl)methy-
l)thieno[3,2-d]pyrimidin-4(3H)-one (I-9, 20 mg, 44%). LCMS: (ESI)
m/z 494.11 [M+H].
Method B
Example 3
(E)-4-(dimethylamino)-N-(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrim-
idin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)but-2-enamide
(I-11)
##STR00038##
[0516] Step 1. tert-Butyl
(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-
-hydroxypiperidin-1-yl)-5-oxopentyl)carbamate
[0517] In a 10-mL vial was added
7-(4-fluorophenyl)-3-((4-hydroxypiperidin-4-yl)methyl)thieno[3,2-d]pyrimi-
din-4(3H)-one hydrochloric acid salt (Intermediate 2-1, 33 mg,
0.091 mmol), 5-((tert-butoxycarbonyl)amino)pentanoic acid (24 mg,
0.110 mmol), HATU (38 mg, 0.100 mmol), DMF (0.913 ml) and
triethylamine (0.051 ml, 0.365 mmol). The resulting mixture was
stirred for 8 h at room temperature then diluted with ethyl acetate
(100 mL) and washed with saturated aqueous ammonium chloride (25
mL) and saturated aqueous sodium bicarbonate (25 mL). The organic
layer was dried over anhydrous magnesium sulfate, filtered,
concentrated under reduced pressure and purified by column
chromatography (75 to 100% ethyl acetate) to afford tert-butyl
(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-
-hydroxypiperidin-1-yl)-5-oxopentyl)carbamate (40 mg, 78%). LCMS:
(ESI) m/z 559.04 [M+H].
Step 2.
3-((1-(5-Aminopentanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluo-
rophenyl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloric acid
salt
[0518] To a 50-mL round-bottomed flask was added tert-butyl
(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-
-hydroxypiperidin-1-yl)-5-oxopentyl)carbamate (Step 1, 40 mg, 0.071
mmol) and hydrochloric acid (4.0 M in 1,4-dioxane, 0.952 mmol,
0.238 ml). The reaction mixture was stirred for 2 h at room
temperature and then concentrated under reduced pressure to afford
3-((1-(5-aminopentanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluoropheny-
l)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloric acid salt (35 mg,
100%). LCMS: (ESI) m/z 458.99 [M+H].
Step 3.
(E)-4-(dimethylamino)-N-(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-
-d]pyrimidin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)but-2-e-
namide
[0519] To a 10-mL vial was added
3-((1-(5-aminopentanoyl)-4-hydroxypiperidin-4-yl)methyl)-7-(4-fluoropheny-
l)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloric acid salt (Step 2,
35 mg, 0.076 mmol), (E)-4-(dimethylamino)but-2-enoic acid
hydrochloric acid sat (13 mg, 0.076 mmol), HATU (0.032 g, 0.084
mmol), DMF (0.763 ml) and triethylamine (0.043 ml, 0.305 mmol). The
reaction mixture was stirred for 8 h and diluted with ethyl acetate
(100 mL). The organic layer was washed with saturated aqueous
ammonium chloride (25 mL) and saturated aqueous sodium bicarbonate
(25 mL). The organic layer was dried over anhydrous magnesium
sulfate. The solids were filtered and the solvent removed under
reduced pressure. The residue was purified by preparative HPLC to
afford
(E)-4-(dimethylamino)-N-(5-(4-((7-(4-fluorophenyl)-4-oxothieno[3,2-d]pyri-
midin-3(4H)-yl)methyl)-4-hydroxypiperidin-1-yl)-5-oxopentyl)but-2-enamide
(I-11, 10 mg, 21%). LCMS: (ESI) m/z 570.34 [M+H]. HPLC Column:
Waters XBridge BEH C18 OBD Prep Column, 130 .ANG., 5 .mu.m, 19
mm.times.50 mm. Mobile phase A: 0.1% aqueous formic acid/Mobile
phase B: acetonitrile. Gradient: 15% B to 65% B over 8 min. Flow
rate: 23 mL/min. Detector: 220 and 254 nm.
Method C
Example 4
3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-propylthieno[2,-
3-d]pyrimidin-4(3H)-one (I-4)
##STR00039##
[0520] Step 1. tert-Butyl
4-hydroxy-4-((4-oxo-6-propylthieno[2,3-d]pyrimidin-3(4H)-yl)methyl)piperi-
dine-1-carboxylate
[0521] To a solution of 6-propylthieno[2,3-d]pyrimidin-4(3H)-one
(12 mg, 0.06 mmol) and tert-butyl
1-oxa-6-azaspiro[2.5]octane-6-carboxylate (16 mg, 0.075 mmol) in
DMF (0.3 mL) was added cesium carbonate (59 mg, 0.18 mmol). The
reaction mixture was stirred at 80.degree. C. for 16 h, then cooled
to room temperature, diluted with ethyl acetate (0.5 mL) and washed
with water (0.5 mL). The organic layer was concentrated under
reduced pressure to afford tert-butyl
4-hydroxy-4-((4-oxo-6-propylthieno[2,3-d]pyrimidin-3(4H)-yl)methyl)piperi-
dine-1-carboxylate, which was used without further purification.
LCMS: (ESI) m/z 430.31 [M+Na].
Step 2.
3-((4-Hydroxypiperidin-4-yl)methyl)-6-propylthieno[2,3-d]pyrimidin-
-4(3H)-one trifluoroacetic acid salt
[0522] To a solution of tert-butyl
4-hydroxy-4-((4-oxo-6-propylthieno[2,3-d]pyrimidin-3(4H)-yl)methyl)piperi-
dine-1-carboxylate (Step 1) in 1,2-dichloroethane (0.3 mL) was
added trifluoroacetic acid (0.046 mL, 0.80 mmol). The reaction
mixture was stirred at 50.degree. C. for 2 h and concentrated under
reduced pressure to afford
3-((4-hydroxypiperidin-4-yl)methyl)-6-propylthieno[2,3-d]pyrimi-
din-4(3H)-one trifluoroacetic acid salt, which was used without
further purification. LCMS: (ESI) m/z 308.23 [M+H].
Step 3.
3-((4-Hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-propylt-
hieno[2,3-d]pyrimidin-4(3H)-one
[0523] To a suspension of
3-((4-hydroxypiperidin-4-yl)methyl)-6-propylthieno[2,3-d]pyrimidin-4(3H)--
one trifluoroacetic acid salt (Step 2) in 1,2-dichloroethane (0.3
mL) was added 3-phenylbutanoic acid (0.2 M in 1,2-dichloroethane,
0.360 mL, 0.072 mmol), DIPEA (0.052 mL, 0.3 mmol) and HATU (27 mg,
0.072 mmol). The reaction mixture was stirred at 50.degree. C. for
16 h, then cooled to room temperature, diluted with dichloromethane
(0.5 mL) and washed with water (0.5 mL). The organic layer was
concentrated under reduced pressure and the residue was purified by
preparative HPLC to afford
3-((4-hydroxy-1-(3-phenylbutanoyl)piperidin-4-yl)methyl)-6-propylthieno[2-
,3-d]pyrimidin-4(3H)-one (I-4, 4.8 mg, 18% over three steps). LCMS
(ESI) m/z 454.26 [M+H]. HPLC Column: XBridge BEH C18 OBD Prep
Column, 130 .ANG., 5 .mu.m, 19 mm.times.50 mm. Mobile phase A:
Water with 0.1% ammonium hydroxide./Mobile phase B: Acetonitrile
with 0.1% ammonium hydroxide. Gradient: 50% B to 100% B over 6 min.
Flow rate: 23 mL/min. Detector: 220 and 254 nm
Biochemical Assays
Example 5
USP7 Assay (Ubitquin-Rhodamine110 Assay)
[0524] Each assay was performed in a final volume of 15 .mu.L in
assay buffer containing 20 mM Tris-HCl (pH 8.0, (1M Tris-HCl, pH
8.0 solution; Corning 46-031-CM)), 1 mM GSH (L-Glutathione reduced;
Sigma #G4251), 0.03% BGG (0.22 .mu.M filtered, Sigma, #G7516-25G),
and 0.01% Triton X-100 (Sigma, #T9284-10L). Nanoliter quantities of
either an 8-point or 10-point, 3-fold serial dilution in DMSO was
pre-dispensed into assay plates (Perkin Elmer, ProxiPlate-384 F
Plus, #6008269) for a final test concentration range of either 25
.mu.M to 11 nM or 25 .mu.M to 1.3 nM, respectively. The final
concentration of the enzyme (USP7, construct USP7 (208-1102) 6*His,
Viva Biotech) in the assay was 62.5 pM. Final substrate (Ub-Rh110;
Ubiquitin-Rhodamine 110, R&D Systems #U-555) concentration was
25 nM with [Ub-Rh110]<<Km. 5 .mu.L of 2.times. enzyme was
added to assay plates (pre-stamped with compound) preincubated with
USP7 for 30 min and then 5 .mu.L of 2.times.Ub-Rh110 was added to
assay plates. Plates were incubated stacked for 20 min at room
temperature before addition of 5 .mu.L of stop solution (final
concentration of 10 mM citric acid in assay buffer (Sigma,
#251275-500G)). Fluorescence was read on the Envision (Excitation
at 485 nm and Emission at 535 nm; Perkin Elmer) or on the PheraSTAR
(Excitation at 485 nm and Emission at 535 nm; BMG Labtech).
[0525] Data from USP7 Assay was reported as percent inhibition
(inh) compared with control wells based on the following equation:
% inh=1-((FLU-Ave.sub.Low)/(Ave.sub.High-Ave.sub.Low)) where
FLU=measured Fluorescence; Ave.sub.Low=average Fluorescence of no
enzyme control (n=16); and Ave.sub.High=average Fluorescence of
DMSO control (n=16). IC.sub.50 values were determined by curve
fitting of the standard 4 parameter logistic fitting algorithm
included in the Activity Base software package: IDBS XE Designer
Model205. Data is fitted using the Levenburg Marquardt algorithm.
IC.sub.50 data from USP7 Assays for the compounds of the disclosure
is shown in the Table below.
TABLE-US-00001 TABLE 1 USP7 activity of compounds of the disclosure
in USP7 assay. Interme- LCMS: HPLC Compound diate In (ESI) m/z
retention No.: Method Synthesis [M + 1] time/min USP7_IC50 I-1 C
412.2 1.12 +++ I-2 C 466.29 1.55 + I-3 C 452.21 1.42 ++ I-4 C
454.26 1.49 +++ I-5 C 426.16 1.24 ++ I-6 C 426.16 1.23 ++++ I-7 C
440.18 1.36 ++++ I-8 C 440.18 1.4 + I-10 A 2-1 464.08 1.38 ++ I-9 A
2-1 494.11 1.39 ++ I-11 A, B 2-1 570.34 0.98 ++ I-12 A, B 2-1 556.3
0.91 ++ ++++ indicates an IC.sub.50 of less than about 0.3 .mu.M,
+++ indicates an IC.sub.50 between about 0.3 .mu.M and about 1
.mu.M, ++ indicates an IC.sub.50 between about 1 .mu.M and about 10
.mu.M, and + indicates an IC.sub.50 greater than 10 .mu.M.
Equivalents
[0526] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically
herein. Such equivalents are intended to be encompassed in the
scope of the following claims.
* * * * *